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Inflammasome activation in traumatic brain injury and Alzheimer's disease

  • Nathan H. Johnson
    Affiliations
    Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Juan Pablo de Rivero Vaccari
    Affiliations
    The Miami Project to Cure Paralysis, Miami, FL, USA

    Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Center for Cognitive Neuroscience and Aging, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Helen M. Bramlett
    Affiliations
    The Miami Project to Cure Paralysis, Miami, FL, USA

    Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
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  • Robert W. Keane
    Affiliations
    The Miami Project to Cure Paralysis, Miami, FL, USA

    Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA
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  • W. Dalton Dietrich
    Correspondence
    Reprint requests: W. Dalton Dietrich, PhD, Scientific Director, The Miami Project to Cure Paralysis, Professor of Neurological Surgery, Neurology, Biomedical Engineering and Cell Biology, University of Miami, Leonard M. Miller School of Medicine, 1095 NW 14th Terrace, Suite 2-30, Miami, FL 33136-1060.
    Affiliations
    The Miami Project to Cure Paralysis, Miami, FL, USA

    Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Center for Cognitive Neuroscience and Aging, University of Miami Miller School of Medicine, Miami, FL, USA
    Search for articles by this author
Open AccessPublished:September 04, 2022DOI:https://doi.org/10.1016/j.trsl.2022.08.014

      ABSTRACT

      Traumatic brain injury (TBI) and Alzheimer's disease (AD) represent 2 of the largest sources of death and disability in the United States. Recent studies have identified TBI as a potential risk factor for AD development, and numerous reports have shown that TBI is linked with AD associated protein expression during the acute phase of injury, suggesting an interplay between the 2 pathologies. The inflammasome is a multi-protein complex that plays a role in both TBI and AD pathologies, and is characterized by inflammatory cytokine release and pyroptotic cell death. Products of inflammasome signaling pathways activate microglia and astrocytes, which attempt to resolve pathological inflammation caused by inflammatory cytokine release and phagocytosis of cellular debris. Although the initial phase of the inflammatory response in the nervous system is beneficial, recent evidence has emerged that the heightened inflammatory response after trauma is self-perpetuating and results in additional damage in the central nervous system. Inflammasome-induced cytokines and inflammasome signaling proteins released from activated microglia interact with AD associated proteins and exacerbate AD pathological progression and cellular damage. Additionally, multiple genetic mutations associated with AD development alter microglia inflammatory activity, increasing and perpetuating inflammatory cell damage. In this review, we discuss the pathologies of TBI and AD and how they are impacted by and potentially interact through inflammasome activity and signaling proteins. We discuss current clinical trials that target the inflammasome to reduce heightened inflammation associated with these disorders.

      Abbreviations:

      (amyloid beta), AD (Alzheimer's disease), AIM2 (absent in melanoma 2), ALR (AIM2 like receptor), ApoE4 (apolipoprotein E-4), APP (amyloid precursor protein), ASC (apoptosis-associated speck-like protein containing a caspase recruiting domain), ATP (adenosine tri-phosphate), BACE (β-secretase), BBB (blood-brain barrier), CARD (C terminus caspase recruitment domain), CDC (U.S. Centers for Disease Control and Prevention), CNS (central nervous system CRP, C-reactive protein), DAM (disease associated microglia), DAMPs (damage associated molecular patterns), GFAP (glial fibrillary acidic protein), Glu (glutamate), GSDMD (gasdermin-D), IL (interleukin), LPS (lipopolysaccharide), MAPT (microtubule associated protein tau), NF-κB (nuclear factor-κB), NOD (nucleotide oligomerizing domain), NLR (NOD-like receptor), NLRC (NLR- containing caspase domain NLRP, NLR- containing pyrin domain), PAMPs (pathogen associated molecular patterns), PRR (pattern recognition receptors), PSEN (presenilin), pTau (hyperphosphorylated tau), ROS (reactive oxygen species), RhoA (Ras homolog family member A), TBI (traumatic brain injury), TLR (Toll-like receptors), TREM2 (triggering receptor expressed on myeloid cells 2)

      Introduction

      Traumatic Brain Injury (TBI) is a significant source of disability and death in the United States,
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      • Xu L
      • Basavaraju SV
      • et al.
      Surveillance for traumatic brain injury-related deaths–United States, 1997-2007.
      with an average of 1.7 million Americans. It is reported that 30% of people who suffer a moderate TBI report worsening symptoms over a 5 year period, with deficits in learning and memory as one of the major disabling results.
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      • Sigford B.
      Persistent problems after traumatic brain injury: the need for long-term follow-up and coordinated care.
      ,
      Prevention CfDCa
      Surveillance report of traumatic brain injury-related hospitalizations and deaths by age group, sex, and mechanism of injury—United States, 2016 and 2017.
      These symptoms are a result of the initial acute trauma to the brain as well as homeostatic changes in the central nervous system (CNS) and chronic inflammation.
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      • Boles JA
      • Wagner AK.
      Chronic inflammation after severe traumatic brain injury: characterization and associations with outcome at 6 and 12 months postinjury.
      TBI presents as a potent risk factor for the development of additional pathologies throughout the CNS and systemically.
      • Kerr N
      • de Rivero Vaccari JP
      • Dietrich WD
      • Keane RW.
      Neural-respiratory inflammasome axis in traumatic brain injury.
      • Kerr NA
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      • Weaver C
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      • Ahmed T
      • Keane RW.
      Enoxaparin attenuates acute lung injury and inflammasome activation after traumatic brain injury.
      For instance, TBI is a potent underlying contributor to the pathology of Alzheimer's disease (AD).
      • Zysk M
      • Clausen F
      • Aguilar X
      • Sehlin D
      • Syvanen S
      • Erlandsson A
      Long-term effects of traumatic brain injury in a mouse model of Alzheimer's disease.
      AD is a neurodegenerative and psychiatric disorder that is one of the most common forms of dementia.
      • Zysk M
      • Clausen F
      • Aguilar X
      • Sehlin D
      • Syvanen S
      • Erlandsson A
      Long-term effects of traumatic brain injury in a mouse model of Alzheimer's disease.
      AD pathology is driven by a combination of genetic and environmental factors.
      • Heneka MT
      • Carson MJ
      • El Khoury J
      • et al.
      Neuroinflammation in Alzheimer's disease.
      There are 2 major pathological hallmarks of AD; the formation and accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles (pTau) that result in chronic inflammation and neuronal loss.
      • Hanslik KL
      • Ulland TK.
      The role of microglia and the nlrp3 inflammasome in Alzheimer's disease.
      According to the United States Centers for Disease Control and Prevention (CDC), individuals with a history of moderate TBI have a 2.3 times greater risk of developing AD,
      Prevention CfDCa
      Surveillance report of traumatic brain injury-related hospitalizations and deaths by age group, sex, and mechanism of injury—United States, 2016 and 2017.
      and this risk may be due to the chronic nature of neuroinflammation after TBI. Moreover, there are numerous pathological features shared between TBI and AD, but most notable is the chronic neuroinflammatory response that is mediated in part by persistent inflammasome activation of the innate immune response.
      The inflammasome is a multi-protein complex that activates the proinflammatory cytokines interleukin (IL)-1β and IL-18 upon activation of caspase-1, resulting in the cell death process of pyroptosis. In TBI, several recent studies have documented increased inflammasome activity after injury, primarily occurring in activated microglia.
      • Heneka MT
      • Carson MJ
      • El Khoury J
      • et al.
      Neuroinflammation in Alzheimer's disease.
      ,
      • Lee SW
      • de Rivero Vaccari JP
      • Truettner JS
      • Dietrich WD
      • Keane RW.
      The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.
      In AD, Aβ accumulation within the CNS activates microglia resulting in the release of IL-1β.
      • Heneka MT
      • McManus RM
      • Latz E.
      Inflammasome signalling in brain function and neurodegenerative disease.
      Furthermore, Aβ plaques form as a result of Aβ monomers binding to inflammasome components.
      • Venegas C
      • Kumar S
      • Franklin BS
      • et al.
      Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer's disease.
      Recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia.
      • Ising C
      • Venegas C
      • Zhang S
      • et al.
      NLRP3 inflammasome activation drives tau pathology.
      These findings collectively suggest that the main pathomechanisms of AD may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate AD pathology.
      In this review, we discuss the pathophysiology of TBI and introduce relevant clinical and experimental findings involved with TBI induced inflammasome activity and pathology. Furthermore, we discuss TBI as a risk factor for AD development, and how these 2 pathologies interact mechanistically via inflammasome activity. Finally, we discuss current translational studies and potential therapeutic pathways for development of therapeutics that target inflammasome activation in TBI and AD pathologies.

      The innate immune system

      The pathophysiological processes underlying trauma are diverse and complex. Cell death, structural damage, inflammation, swelling, and infection often result from physical trauma and are either transitory components of the initial trauma and recovery or alter homeostasis in more chronic pathology. The effects of TBI are not transient, but result in chronic alterations to the CNS environment, including structural changes and a persistent elevation of inflammatory activity.
      • Lee SW
      • Gajavelli S
      • Spurlock MS
      • et al.
      Microglial inflammasome activation in penetrating ballistic-like brain injury.
      • Titus DJ
      • Johnstone T
      • Johnson NH
      • et al.
      Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury.
      • Griesbach GS
      • Masel BE
      • Helvie RE
      • Ashley MJ.
      The impact of traumatic brain injury on later life: effects on normal aging and neurodegenerative diseases.
      • Bramlett HM
      • Dietrich WD.
      Long-term consequences of traumatic brain injury: current status of potential mechanisms of injury and neurological outcomes.
      One such physiological process that has been shown to be involved in acute and chronic pathology is the innate immune response.
      Evolutionarily speaking, the innate immune system is one of the oldest forms of defense from invading organisms and cellular damage and is conserved in all forms of complex cellular life.
      • VanItallie TB.
      Alzheimer's disease: innate immunity gone awry?.
      The innate immune system is composed of both physical defenses, such as the skin and epithelia, and cellular agents, such as macrophages and neutrophils.
      • Janeway Jr, CA
      • Medzhitov R
      Innate immune recognition.
      The innate immune system utilizes genetically encoded pattern recognition receptors (PRR) to detect infectious pathogens, unwanted foreign matter, and cellular damage. PRR such as Toll-like receptors (TLR) and nucleotide oligomerizing domain (NOD)-like receptors (NLR) facilitate the innate immune system to recognize damage associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs), which induce macrophages to immediately react and shift to a mobile and inflammatory phenotype thus mediating phagocytosis of invaders and the secretion of inflammatory signaling proteins to alert nearby cells of potential harm.
      • Heneka MT
      • McManus RM
      • Latz E.
      Inflammasome signalling in brain function and neurodegenerative disease.
      ,
      • Janeway Jr, CA
      • Medzhitov R
      Innate immune recognition.
      Similarly, other cells express PRR and recognize DAMPs and PAMPs, triggering activation of the innate immune response, including inflammasomes in neurons,
      • Abulafia DP
      • de Rivero Vaccari JP
      • Lozano JD
      • Lotocki G
      • Keane RW
      • Dietrich WD.
      Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice.
      • Cyr B
      • Hadad R
      • Keane RW
      • de Rivero Vaccari JP.
      The role of non-canonical and canonical inflammasomes in inflammaging.
      • de Rivero Vaccari JP
      • Lotocki G
      • Alonso OF
      • Bramlett HM
      • Dietrich WD
      • Keane RW.
      Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury.
      • de Rivero Vaccari JP
      • Lotocki G
      • Marcillo AE
      • Dietrich WD
      • Keane RW.
      A molecular platform in neurons regulates inflammation after spinal cord injury.
      astrocytes,
      • Minkiewicz J
      • de Rivero Vaccari JP
      • Keane RW.
      Human astrocytes express a novel NLRP2 inflammasome.
      microglia
      • Lee SW
      • de Rivero Vaccari JP
      • Truettner JS
      • Dietrich WD
      • Keane RW.
      The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.
      ,
      • Lee SW
      • Gajavelli S
      • Spurlock MS
      • et al.
      Microglial inflammasome activation in penetrating ballistic-like brain injury.
      and oligodendrocytes.
      • Maturana CJ
      • Aguirre A
      • Saez JC.
      High glucocorticoid levels during gestation activate the inflammasome in hippocampal oligodendrocytes of the offspring.

      Immunological moderators of CNS injury and disease

      The CNS environment has been traditionally considered to be immunologically privileged.
      • Harris MG
      • Hulseberg P
      • Ling C
      • et al.
      Immune privilege of the CNS is not the consequence of limited antigen sampling.
      ,
      • Frederick NM
      • Tavares GA
      • Louveau A.
      Neuroimmune signaling at the brain borders.
      The blood-brain barrier (BBB), numerous antigen presenting cells, and a wide range of anti-inflammatory modulators participate in the brain's immune response in which inflammation is highly regulated.
      • Harris MG
      • Hulseberg P
      • Ling C
      • et al.
      Immune privilege of the CNS is not the consequence of limited antigen sampling.
      Recent studies identified that a large array of neuroimmune interactions occurs at the CNS borders in the meningeal lymphatic system and that dysfunction of this system exacerbates TBI pathologies.
      • Frederick NM
      • Tavares GA
      • Louveau A.
      Neuroimmune signaling at the brain borders.
      ,
      • Bolte AC
      • Lukens JR.
      Neuroimmune cleanup crews in brain injury.
      Of all these mechanisms, microglia have been identified as key players in the CNS response to trauma. Interestingly, these cells play dual roles as first responders to CNS illness and injury, but also act to maintain neural homeostasis and plasticity.
      • Prinz M
      • Masuda T
      • Wheeler MA
      • Quintana FJ.
      Microglia and central nervous system-associated macrophages-from origin to disease modulation.
      ,
      • Augusto-Oliveira M
      • Arrifano GP
      • Delage CI
      • Tremblay ME
      • Crespo-Lopez ME
      • Verkhratsky A.
      Plasticity of microglia.
      In the healthy CNS environment, microglia are in a “resting” state and are identified morphologically by long processes, which sample the environment to detect deleterious changes to homeostasis.
      • Torres-Platas SG
      • Comeau S
      • Rachalski A
      • et al.
      Morphometric characterization of microglial phenotypes in human cerebral cortex.
      It is in the resting state microglia also clear cellular debris and contribute to the overall plasticity of the CNS through the maintenance of neuronal connections, regulation of neurogenesis, and pruning of synapses.
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      After trauma, TLRs and NLRs on microglia detect PAMPs and DAMPs released by injured cells, and quickly shift to an “activated” state in which they assume a more ameboid morphology and migrate towards the site of injury.
      • Torres-Platas SG
      • Comeau S
      • Rachalski A
      • et al.
      Morphometric characterization of microglial phenotypes in human cerebral cortex.
      ,
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      Microglia are important for maintaining the health of the CNS and aid in the removal of damaged neurons and infections. In addition, they play important roles in secondary pathomechanisms of a variety of CNS disorders and interact with astrocytes and neurons in response to CNS trauma.
      • Donat CK
      • Scott G
      • Gentleman SM
      • Sastre M.
      Microglial activation in traumatic brain injury.
      Microglia are a well-established source of inflammatory activity within the CNS that is primarily regulated by activation and formation of inflammasomes. Activated microglia have traditionally been classified into 2 phenotypes. The M1 form is proinflammatory and expresses pro-inflammatory cytokines and chemokines, while the M2 form is neuroprotective and expresses anti-inflammatory cytokines, neurotropic factors, and resolves the inflammatory activity of the M1 form.
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Alam A
      • Thelin EP
      • Tajsic T
      • et al.
      Cellular infiltration in traumatic brain injury.
      Although these forms are complimentary, studies have shown that the M2 form is short lived after injury, and that the M1 form plays a prevailing role in chronic inflammatory activity after injury.
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Kumar A
      • Alvarez-Croda DM
      • Stoica BA
      • Faden AI
      • Loane DJ.
      Microglial/macrophage polarization dynamics following traumatic brain injury.
      However, recent research has shown that these traditional phenotypic classifications of microglia are not all inclusive, and alternative and intermediate forms may exist.
      • Augusto-Oliveira M
      • Arrifano GP
      • Delage CI
      • Tremblay ME
      • Crespo-Lopez ME
      • Verkhratsky A.
      Plasticity of microglia.
      ,
      • Donat CK
      • Scott G
      • Gentleman SM
      • Sastre M.
      Microglial activation in traumatic brain injury.
      Studies investigating microglia activation after CNS injury or illness have noted that the M1/M2 microglial classification is simplistic, as multipurpose and alternative forms have been identified after injury.
      • Morganti JM
      • Riparip LK
      • Rosi S.
      Call off the Dog(ma): M1/M2 polarization is concurrent following traumatic brain injury.
      ,
      • Wendimu MY
      • Hooks SB.
      Microglia phenotypes in aging and neurodegenerative diseases.
      For example, the anti-inflammatory and regenerative M2 form has been further subdivided into M2a, M2b, M2c
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      ,
      • Zhang L
      • Zhang J
      • You Z.
      Switching of the microglial activation phenotype is a possible treatment for depression disorder.
      and M2d subtypes.
      • Wendimu MY
      • Hooks SB.
      Microglia phenotypes in aging and neurodegenerative diseases.
      ,
      • Lukacova N
      • Kisucka A
      • Kiss Bimbova K
      • et al.
      Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury.
      The M2a form is activated by IL-4 and IL-13 and plays a role in anti-parasitic responses in that it increases scavenger receptors and induces phagocytosis, IL-10 secretion, and tissue growth and repair.
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      ,
      • Lukacova N
      • Kisucka A
      • Kiss Bimbova K
      • et al.
      Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury.
      The M2b form is activated by IL-1R ligands and may form intermediate types that expresses pro- or anti-inflammatory activity through secretion of IL-1β, TNF-α, and IL-10. M2b interacts with B cells and regulates the M2 response that also shares characteristics of M1 microglia.
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      The M2c form, activated by IL-10 and glucocorticoids, is considered to resolve inflammation in that it promotes the cleanup of tissue after inflammatory activity is reduced.
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      ,
      • Lukacova N
      • Kisucka A
      • Kiss Bimbova K
      • et al.
      Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury.
      The M2d form is unique in that it is derived from the M1 form and is alternatively activated through IL-6 and adenosine receptors and is anti-inflammatory and angiogenic in nature.
      • Lukacova N
      • Kisucka A
      • Kiss Bimbova K
      • et al.
      Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury.
      ,
      • Amici SA
      • Dong J
      • Guerau-de-Arellano M
      Molecular mechanisms modulating the phenotype of macrophages and microglia.
      Beyond the classical M1/M2 classifications, recent studies have indicated that microglia classification may be better defined along a shifting spectrum of inflammatory activity, and that microglia should instead be defined by multiple factors such as genetic expression or by the identification of multiple surface markers.
      • Gottlieb A
      • Toledano-Furman N
      • Prabhakara KS
      • et al.
      Time dependent analysis of rat microglial surface markers in traumatic brain injury reveals dynamics of distinct cell subpopulations.
      ,
      • Boche D
      • Gordon MN.
      Diversity of transcriptomic microglial phenotypes in aging and Alzheimer's disease.
      Although, many current studies still use the M1/M2 classification colloquially to refer to pro-inflammatory vs anti-inflammatory microglia, new classifications are especially important in AD pathology. A new form of disease associated microglia (DAM), defined by the expression of multiple AD associated genes, is thought to play an integral role in AD pathology progression.
      • Boche D
      • Gordon MN.
      Diversity of transcriptomic microglial phenotypes in aging and Alzheimer's disease.
      (Table Ⅰ).
      Table ⅠMicroglia classifications
      Microglia typeActivatorsFunctionalityPhysiological responseSources
      M1LPS, IFN-γProinflammatoryIL-1β, TNF-α, ROS
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Alam A
      • Thelin EP
      • Tajsic T
      • et al.
      Cellular infiltration in traumatic brain injury.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      M2aIL-4, IL-13Anti-inflammatoryIncreased scavenger receptors
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      ,
      • Lukacova N
      • Kisucka A
      • Kiss Bimbova K
      • et al.
      Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury.
      IL-10
      M2bIL-1R ligandsBothIL-1β, TNF-α, IL-10
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      B cell class switching
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      M2cIL-10, glucocorticoidsAnti-inflammatoryIncreased phagocytosis
      • Loane DJ
      • Kumar A.
      Microglia in the TBI brain: The good, the bad, and the dysregulated.
      ,
      • Huang X
      • You W
      • Zhu Y
      • Xu K
      • Yang X
      • Wen L.
      Microglia: a potential drug target for traumatic axonal injury.
      ,
      • Lukacova N
      • Kisucka A
      • Kiss Bimbova K
      • et al.
      Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury.
      Promote structural repair
      M2dIL-6, AdenosineAnti-inflammatoryPro-angiogenic
      • Wendimu MY
      • Hooks SB.
      Microglia phenotypes in aging and neurodegenerative diseases.
      ,
      • Lukacova N
      • Kisucka A
      • Kiss Bimbova K
      • et al.
      Glial-neuronal interactions in pathogenesis and treatment of spinal cord injury.
      ,
      • Amici SA
      • Dong J
      • Guerau-de-Arellano M
      Molecular mechanisms modulating the phenotype of macrophages and microglia.
      DAMTREM2, PSEN, ApoEDysfunctionalIncreased autophagy and Aβ phagocytosis
      Increased cytokine expression
      • Orr ME
      • Oddo S.
      Autophagic/lysosomal dysfunction in Alzheimer's disease.
      • Hemonnot AL
      • Hua J
      • Ulmann L
      • Hirbec H.
      Microglia in Alzheimer disease: well-known targets and new opportunities.
      Excessive dendritic pruning
      Microglia interact with astrocytes and neurons in response to CNS trauma. Astrocytes and microglia maintain CNS homeostasis and modulate inflammatory cytokine expression regulated by assembly of the inflammasome. Astrocytes are the most numerous cell type in the brain
      • Verkhratsky A
      • Parpura V.
      Recent advances in (patho)physiology of astroglia.
      and function in maintaining the CNS environment
      • Verkhratsky A
      • Parpura V.
      Recent advances in (patho)physiology of astroglia.
      and together with neurons maintain ionic and water balances, regulate blood flow, maintain the BBB, and modulate synaptic transmission.
      • Verkhratsky A
      • Parpura V.
      Recent advances in (patho)physiology of astroglia.
      • Belanger M
      • Magistretti PJ.
      The role of astroglia in neuroprotection.
      • Miller SJ.
      Astrocyte heterogeneity in the adult central nervous system.
      Interestingly, astrocytes are similar to microglia in that they also have long processes that sample their environments for changes in homeostasis. Astrocytes form complex networks of gap junctions and closely adhere to neurons, and through unique end-feet adhere to blood vessels forming the BBB.
      • Bolte AC
      • Lukens JR.
      Neuroimmune cleanup crews in brain injury.
      ,
      • Belanger M
      • Magistretti PJ.
      The role of astroglia in neuroprotection.
      Astrocytes maintain homeostasis through crosstalk with neurons via glutamatergic and GABAergic neurotransmission, calcium signaling, and ionic buffering.
      • Verkhratsky A
      • Parpura V.
      Recent advances in (patho)physiology of astroglia.
      • Belanger M
      • Magistretti PJ.
      The role of astroglia in neuroprotection.
      • Miller SJ.
      Astrocyte heterogeneity in the adult central nervous system.
      In the event of trauma or infection, astrocytes become activated (astrogliosis), as indicated by an increase of the cytoskeletal protein glial fibrillary acidic protein (GFAP), and like microglia, secrete numerous inflammatory products, including cytokines and chemokines such as IL-1β, TNF-α, growth factors and reactive oxygen species.
      • Belanger M
      • Magistretti PJ.
      The role of astroglia in neuroprotection.
      ,
      • Sofroniew MV.
      Astrogliosis.
      There are numerous triggers of astrogliosis such as DAMPs from damaged cells, cytokines from microglia, Aβ from neurons, albumin from BBB disruption, and synaptic glutamate and adenosine tri-phosphate (ATP), the exact nature of astrocytic activation is still not well understood.
      • Sofroniew MV.
      Astrogliosis.
      ,
      • Rajesh Y
      • Kanneganti T-D.
      Innate Immune Cell Death in Neuroinflammation and Alzheimer’s disease.

      Inflammasome activation and assembly

      The inflammasome (Fig 1) is a multi-protein complex formed as part of the innate immune response. Inflammasomes are identified by their sensor protein, which contains either an NLR, an absent in melanoma 2 (AIM2) like receptor (ALR), or pyrin.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Sharma D
      • Kanneganti TD.
      The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation.
      The NLR group of inflammasomes includes NLRP1, NLRP3, and NLRC4, and is further classified by whether their nucleotide binding regions have a pyrin (NLRP) or caspase (NLRC) activation and recruitment domain.
      • Sharma D
      • Kanneganti TD.
      The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation.
      The inflammasome complex is composed of caspase-1 and typically contains an adaptor protein known as apoptosis-associated speck-like protein containing a caspase recruiting domain (ASC).
      • Malik A
      • Kanneganti TD.
      Inflammasome activation and assembly at a glance.
      Upon inflammasome activation, the oligomerization of ASC allows for the binding and subsequent activation of pro-caspase-1.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Malik A
      • Kanneganti TD.
      Inflammasome activation and assembly at a glance.
      ,
      • Van Opdenbosch N
      • Lamkanfi M.
      Caspases in cell death, inflammation, and disease.
      Caspase-1 activation leads to the cleavage and activation of IL-1β and IL-18, along with the formation of the pyroptotic pore through cleavage of gasdermin-D (GSDMD).
      • Van Opdenbosch N
      • Lamkanfi M.
      Caspases in cell death, inflammation, and disease.
      ,
      • Andreeva L
      • David L
      • Rawson S
      • et al.
      NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation.
      The end result is pyroptotic cell death and the release of inflammatory cytokines along with the components of the intercellular environment into the extracellular space (Fig 1).
      Fig 1
      Fig 1Inflammasome activation and formation. The NLRP3 inflammasome is activated by numerous triggers and by 2 distinct pathways. The canonical pathway is activated first by TLRs that detect the priming signal (dashed lines) which increases transcription of an inflammasome sensor and cytokine RNA through NF-kB signaling. This is followed by an activating signal including: PAMPs, DAMPs, crystalline matter, K+ efflux, ROS, and external ATP (solid lines) which activates the inflammasome sensor protein, pro-caspase-1, and ASC to form the inflammasome complex. Complex formation allows for the self-activation and cleavage of caspase-1 which in turn cleaves pro-IL-1β and pro-IL-18. Additionally, caspase-1 will cleave GSDMD allowing the N terminus to form the pyroptotic pore after which the cell undergoes pyroptosis, releasing its cellular contents, including the IL-1 inflammatory cytokines. Non-canonical activation occurs through detection of LPS or gram-negative bacteria which also induces transcriptional upregulation and caspase activation. However, this pathway utilizes caspase-4/5 in humans or caspase-11 in murine species, and unlike caspase-1, only cleaves GSDMD to form the pyroptotic pore. Pore formation allows for the release of ATP which activates pannexin channels, resulting in K+ efflux and subsequent NLRP3 activation.
      Activation of the inflammasome is specific to the respective sensor's trigger. The NLRP1 sensor contains a function-to-find domain, and a C terminus caspase recruitment domain (CARD) and is activated by microbial associated agents such as Bacillus anthrax lethal toxin, changes in cellular ATP levels, and double stranded RNA.
      • Bauernfried S
      • Scherr MJ
      • Pichlmair A
      • Duderstadt KE
      • Hornung V.
      Human NLRP1 is a sensor for double-stranded RNA.
      NLRP1 binds caspase-1 directly or with the adapter, ASC.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Sharma D
      • Kanneganti TD.
      The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation.
      ,
      • Chavarria-Smith J
      • Vance RE.
      The NLRP1 inflammasomes.
      ,
      • Ravichandran KA
      • Heneka MT.
      Inflammasome activation in neurodegenerative diseases.
      The NLRP3 sensor is unique in that it is activated through numerous triggers and by 2 distinct pathways. Traditional activation is through the canonical pathway in response to the detection of numerous triggers including PAMPS, DAMPS, extracellular ATP, increases in intracellular calcium, mitochondrial dysfunction, and cellular potassium efflux.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Giza CC
      • Hovda DA.
      The neurometabolic cascade of concussion.
      • O'Brien WT
      • Pham L
      • Symons GF
      • Monif M
      • Shultz SR
      • McDonald SJ.
      The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target.
      • Clauzure M
      • Valdivieso AG
      • Dugour AV
      • et al.
      NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (CASP1) modulation by intracellular Cl(-) concentration.
      The alternative pathway of activation or noncanonical pathway is activated by lipopolysaccharide (LPS), utilizing caspase-4/5 in humans or caspase 11 in mice.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Kesavardhana S
      • Malireddi RKS
      • Kanneganti TD.
      Caspases in cell death, inflammation, and pyroptosis.
      LPS detection results in the caspase cleavage of GSDMD and formation of the pyroptotic pore which results in ATP release and potassium efflux and subsequent activation of NLRP3.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Downs KP
      • Nguyen H
      • Dorfleutner A
      • Stehlik C.
      An overview of the non-canonical inflammasome.
      The NLRC4 sensor is activated indirectly by proteins that detect bacterial components such as flagellin and needle proteins and binds caspase-1 directly to the CARD or with ASC.
      • Sharma D
      • Kanneganti TD.
      The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation.
      ,
      • Malik A
      • Kanneganti TD.
      Inflammasome activation and assembly at a glance.
      ,
      • Ravichandran KA
      • Heneka MT.
      Inflammasome activation in neurodegenerative diseases.
      ,
      • Sundaram B
      • Kanneganti TD.
      Advances in understanding activation and function of the NLRC4 inflammasome.
      NLRP6 is activated by gram positive bacteria, such as listeria and S. aureus, and has been shown to form an inflammasome complex containing ASC, caspase-1 and caspase-11.
      • Ghimire L
      • Paudel S
      • Jin L
      • Jeyaseelan S
      The NLRP6 inflammasome in health and disease.
      ,
      • Hara H
      • Seregin SS
      • Yang D
      • et al.
      The NLRP6 inflammasome recognizes lipoteichoic acid and regulates gram-positive pathogen infection.
      Outside of the NLR family is AIM2, which is activated by cytosolic double stranded DNA, is classified by its N terminal pyrin domain and C terminus hematopoietic interferon-inducible nuclear protein with a 200 amino acid repeat domain and requires ASC to bind caspase-1.
      • Sharma D
      • Kanneganti TD.
      The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation.
      ,
      • Malik A
      • Kanneganti TD.
      Inflammasome activation and assembly at a glance.
      ,
      • Adamczak SE
      • de Rivero Vaccari JP
      • Dale G
      • et al.
      Pyroptotic neuronal cell death mediated by the AIM2 inflammasome.
      Along with pyrin which is activated through Ras homolog family member A (RhoA) inactivation and contains a pyrin domain, 2 B-boxes, a coiled-coil domain, and C terminus B30.2 domain.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      • Sharma D
      • Kanneganti TD.
      The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation.
      • Malik A
      • Kanneganti TD.
      Inflammasome activation and assembly at a glance.
      Regardless of the unique trigger or the particular inflammasome in action, the main result of inflammasome activation is to reduce infection through pyroptotic cell death of the affected cell and alert neighboring cells to potential danger.

      The ASC speck

      ASC is a component of the inflammasome that acts as a scaffold of the inflammasome complex. ASC is expressed via the PYCARD gene and is structurally composed of pyrin and CARD domains that mediate binding of the inflammasome sensor protein and caspase-1, respectively.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Agrawal I
      • Jha S.
      Comprehensive review of ASC structure and function in immune homeostasis and disease.
      Upon inflammasome activation ASC self-oligomerizes into a 1 μm aggregate known as the ASC speck. ASC speck formation is accompanied by the binding of pro-caspase-1, to amplify the inflammatory activity and inflammatory cytokine production.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • Agrawal I
      • Jha S.
      Comprehensive review of ASC structure and function in immune homeostasis and disease.
      ,
      • Nagar A
      • Rahman T
      • Harton JA.
      The ASC speck and NLRP3 inflammasome function are spatially and temporally distinct.
      Nagar and colleagues found that blocking ASC speck formation using colchicine in cells dosed with nigericin did not prevent inflammasome activation or subsequent cytokine maturation, but rather higher doses of nigericin were required to elicit an inflammasome response.
      • Nagar A
      • Rahman T
      • Harton JA.
      The ASC speck and NLRP3 inflammasome function are spatially and temporally distinct.
      These findings suggest that ASC may not be necessary for inflammasome activation, it increases the efficiency of the inflammasome by lowering the stimulus threshold necessary to induce an inflammasome response. This feature allows for a swifter and stronger response to inflammasome triggers.
      ASC specks are secreted extracellularly and amplify the inflammasome response. In the CNS, ASC specks are taken up by activated microglia that also secrete inflammasome mediated cytokines.
      • Venegas C
      • Heneka MT.
      Inflammasome-mediated innateimmunity in Alzheimer's disease.
      Thus, extracellular ASC specks propagate inflammation after release by pyroptotic cells and are ingested by activated microglia that secrete inflammatory cytokines. Moreover, ASC specks may stimulate and perpetuate inflammation after uptake by neighboring cells through recognition by TLRs. Recent studies by Cyr and colleagues show that increased ASC protein expression in the cortical tissue is associated with the progression of the inflammatory response in aging (inflammaging).
      • Cyr B
      • Hadad R
      • Keane RW
      • de Rivero Vaccari JP.
      The role of non-canonical and canonical inflammasomes in inflammaging.
      Similarly, Kerr and colleagues showed increased ASC protein expression and speck oligomerization in the lung tissue of mice within 4 hours after brain injury that was associated with lung damage after CNS trauma.
      • Kerr NA
      • de Rivero Vaccari JP
      • Abbassi S
      • et al.
      Traumatic brain injury-induced acute lung injury: evidence for activation and inhibition of a neural-respiratory-inflammasome axis.
      Johnson and colleagues also observed increased ASC protein expression in the blood serum of patients with diabetic kidney disease and lupus nephritis and showed that ASC protein levels was a reliable biomarker for predicting respective pathological outcomes with increased levels linked to more deleterious outcomes.
      • Johnson NH
      • Keane RW
      • de Rivero Vaccari JP.
      Renal and inflammatory proteins as biomarkers of diabetic kidney disease and lupus nephritis.
      Within the CNS, Johnson et al further observed this same phenomenon in the blood serum collected from hospitalized TBI patients in which ASC and other inflammasome proteins were likewise elevated after injury.
      • Johnson NH
      • Hadad R
      • Taylor RR
      • et al.
      Inflammatory biomarkers of traumatic brain injury.
      Furthermore, Chen and colleagues identified increased levels of ASC proteins in the thrombolytic cores of patients who suffered ischemic stroke,
      • Chen SH
      • Scott XO
      • Ferrer Marcelo Y
      • et al.
      Netosis and inflammasomes in large vessel occlusion thrombi.
      and Keane and colleagues observed increased ASC and caspase-1 protein expression in patients with multiple sclerosis and that both represented potential biomarkers of pathology.
      • Keane RW
      • Dietrich WD
      • de Rivero Vaccari JP.
      Inflammasome proteins as biomarkers of multiple sclerosis.
      ,
      • Govindarajan V
      • de Rivero Vaccari JP
      • Keane RW.
      Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets.
      Lastly, Scott et al showed that ASC protein levels was increased in the blood serum of patients diagnosed with either AD or mild cognitive impairment, and that ASC protein levels was also a reliable biomarker of the early stages of AD pathology.
      • Scott XO
      • Stephens ME
      • Desir MC
      • Dietrich WD
      • Keane RW
      • de Rivero Vaccari JP.
      The inflammasome adaptor protein ASC in mild cognitive impairment and Alzheimer’s disease.
      Taken together the ASC protein, and the inflammasome appears to play a pivotal role in many CNS diseases and insults, including TBI and AD.

      Pathophysiology of TBI

      TBI includes many different forms of CNS injury. These include concussions from sports, trauma from motor vehicle accidents, pressure damage from explosions, and penetrative trauma from gunshot wounds, and all forms of TBI may possess various levels of severity. The pathology of TBI is traditionally viewed as a 2-part event. The initial impact of trauma is termed the primary injury, while the more chronic damage is known as the secondary injury.
      • Alam A
      • Thelin EP
      • Tajsic T
      • et al.
      Cellular infiltration in traumatic brain injury.
      Primary injury involves the damage caused by the physical blow to the brain, with the effects of injury both focal and diffuse and occurring in a relatively short period of time.
      • Alam A
      • Thelin EP
      • Tajsic T
      • et al.
      Cellular infiltration in traumatic brain injury.
      Upon injury (Fig 2), blunt-force trauma causes immediate cell loss at the epicenter of the injury lesion, along with potential vascular injury, glymphatic/lymphatic dysfunction, edema, and diffuse injury to axons and neuronal networks.
      • Bolte AC
      • Lukens JR.
      Neuroimmune cleanup crews in brain injury.
      ,
      • Jarrahi A
      • Braun M
      • Ahluwalia M
      • et al.
      Revisiting traumatic brain injury: from molecular mechanisms to therapeutic interventions.
      It is during the primary injury that PAMPS and DAMPS are released from damaged and dying cells that play an important role in secondary injury.
      Fig 2
      Fig 2TBI and inflammasome pathology. TBI is a chaotic event in which one strike results in major changes to CNS homeostasis. Upon moderate or severe injury, the cells at the epicenter of the trauma will be destroyed and their contents will be spilled out into the extracellular space as DAMPs. Damaged vasculature at the epicenter will result in breakdown of the BBB, allowing for the infiltration of peripheral immune cells and blood vessels carrying excitatory products such as iron, resulting in oxidative stress. DAMPs will prime neurons for pyroptotic activity while also activating microglia and astrocytes to secrete inflammatory cytokines, encouraging inflammasome formation. Trauma induced depolarization will result in the imbalance of ionic homeostasis, encouraging the uptake of Na+, Ca++, efflux of K+ and resulting Na+/K+ pump activity and inflammasome activation. Ca++ uptake and pump activity results in mitochondrial dysfunction, energy loss and the release of ROS. Encouraging excitatory cell death and/or inflammasome formation resulting in GSDMD pore induced pyroptosis and cytokine release.
      During secondary injury, the multiple pathophysiological cascades are activated by the primary injury that results in disruption of CNS homeostasis and cognitive function, chronically. At the cellular level, (Fig 2) there is a disruption in the ionic balance, resulting in energy shortfalls, dysfunctional microglia, and reactive oxygen species (ROS) production.
      • O'Brien WT
      • Pham L
      • Symons GF
      • Monif M
      • Shultz SR
      • McDonald SJ.
      The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target.
      After moderate or more severe TBI, errant depolarization from injured neurons results in the release of neuroexcitatory glutamate.
      • Giza CC
      • Hovda DA.
      The neurometabolic cascade of concussion.
      Increased glutamate release is associated with worsened pathological outcomes, and results in increased intracellular sodium levels and the release of glutamate at the synaptic bouton which in turn cause a post-synaptic release of potassium ions.
      • Giza CC
      • Hovda DA.
      The neurometabolic cascade of concussion.
      ,
      • Jarrahi A
      • Braun M
      • Ahluwalia M
      • et al.
      Revisiting traumatic brain injury: from molecular mechanisms to therapeutic interventions.
      ,
      • Giza CC
      • Hovda DA.
      The new neurometabolic cascade of concussion.
      Potassium efflux is met with calcium influx resulting in an increase in extracellular potassium and sodium potassium pump activity in an attempt to restore ionic balance.
      • Giza CC
      • Hovda DA.
      The neurometabolic cascade of concussion.
      ,
      • Giza CC
      • Hovda DA.
      The new neurometabolic cascade of concussion.
      Resulting pump activity draws on cellular stores of ATP which may be depleted and not restored as mitochondria attempt to store the large influx of intracellular calcium and in turn become dysfunctional, resulting in hyperglycolysis and buildup of lactate.
      • Giza CC
      • Hovda DA.
      The neurometabolic cascade of concussion.
      ,
      • Giza CC
      • Hovda DA.
      The new neurometabolic cascade of concussion.
      With the combination of increased calcium and decreased ATP, the cell undergoes the enzymatic processes necessary to induce cell death.
      • Giza CC
      • Hovda DA.
      The neurometabolic cascade of concussion.
      PAMPs and DAMPs released by injured or necrotic cells trigger the activation of microglia (Fig 2), which attempt to address the injury through the dual application of increased inflammatory activity to clear damaged cells, along with phagocytic activity and neurotrophic factor release to remove and repair damaged structures.
      • Donat CK
      • Scott G
      • Gentleman SM
      • Sastre M.
      Microglial activation in traumatic brain injury.
      Astrocytes become activated by DAMPs and release inflammatory cytokines, while also migrating to the site of injury forming a densely packed astrocytic scar.
      • Sofroniew MV.
      Astrogliosis.
      ,
      • Jarrahi A
      • Braun M
      • Ahluwalia M
      • et al.
      Revisiting traumatic brain injury: from molecular mechanisms to therapeutic interventions.
      Additionally, disruption of the BBB allows for the invasion of monocytes from outside of the CNS environment, which contribute to overall inflammatory activity from injury.
      • Alam A
      • Thelin EP
      • Tajsic T
      • et al.
      Cellular infiltration in traumatic brain injury.
      BBB damage and vascular inflammation also contributes to TBI pathology through the infiltration of blood directly into the cerebral tissue, resulting in excitotoxicity and oxidative stress from iron-rich red blood cells along with the infiltration of non-resident immune cells, resulting in increased inflammation, oxidative stress, and cell death.
      • Jarrahi A
      • Braun M
      • Ahluwalia M
      • et al.
      Revisiting traumatic brain injury: from molecular mechanisms to therapeutic interventions.
      Finally, disruption of the glymphatic and lymphatic systems is thought to reduce clearance of neurotoxic proteins from the CNS after injury resulting in worsened inflammatory pathology, edema, and cell death.
      • Frederick NM
      • Tavares GA
      • Louveau A.
      Neuroimmune signaling at the brain borders.
      ,
      • Bolte AC
      • Lukens JR.
      Neuroimmune cleanup crews in brain injury.
      Although these effects are seen in traumatic injury settings, they often remain present months to years after injury with chronic inflammatory activity leading to increased neurodegeneration and increased risk for the development of comorbid pathologies.
      Studies have shown that damage to the CNS environment from TBI or stroke have been linked to not only loss of cognitive function, but also to psychiatric and sleep disorders, lung damage, cardiovascular disorders, and disruptions to gastrointestinal system functionality.
      • Kerr NA
      • de Rivero Vaccari JP
      • Abbassi S
      • et al.
      Traumatic brain injury-induced acute lung injury: evidence for activation and inhibition of a neural-respiratory-inflammasome axis.
      ,
      • Kerr NA
      • Sanchez J
      • O’Connor G
      • et al.
      Inflammasome-regulated pyroptotic cell death in disruption of the gut-brain axis after stroke.
      • Pollin KU
      • Samuel I
      • Breneman CB
      • Brewster R
      • Reinhard M
      • Costanzo ME
      The relation of subjective and objective assessment of sleep quality with post concussive symptoms in veterans.
      • Izzy S
      • Chen PM
      • Tahir Z
      • et al.
      Association of traumatic brain injury with the risk of developing chronic cardiovascular, endocrine, neurological, and psychiatric disorders.
      Moreover, although TBI is mainly a pathology imposed from an external source, genetic predisposition has also been implicated as a contributor to primary and secondary injury effects. For example, a recent longitudinal study involving U.S. service members observed increased rates of self-reported decline in cognitive function and psychological wellbeing in participants who sustained a mild TBI and were positive for AD-associated apolipoprotein E-4 (ApoE4).
      • Lange RT
      • Merritt VC
      • Brickell TA
      • et al.
      Apolipoprotein E e4 is associated with worse self-reported neurobehavioral symptoms following uncomplicated mild traumatic brain injury in U.S. military service members.
      Additionally, the AD-associated microglia gene triggering receptor expressed on myeloid cells 2 (TREM2) was shown to be upregulated after TBI in rats and potentially linked to TBI neuropathology along with ApoE.
      • Zhou Y
      • Sun Y
      • Ma QH
      • Liu Y.
      Alzheimer's disease: amyloid-based pathogenesis and potential therapies.
      These findings implicate the importance of genetic predisposition on TBI outcomes while also demonstrating how pathological outcomes are very much dependent on the individual, thus making the TBI population extremely heterogenous.

      TBI and inflammasome activity

      Changes in the extracellular environment, the release of PAMPs and DAMPS, the disruption of the BBB, and activation of microglia, all contribute to the chronic inflammatory response after TBI (Fig 2). PAMPS, DAMPS, increased intracellular calcium, potassium efflux, mitochondrial dysfunction, and extracellular ATP may trigger formation of the NLRP3 inflammasome.
      • Broz P
      • Dixit VM.
      Inflammasomes: mechanism of assembly, regulation and signalling.
      ,
      • O'Brien WT
      • Pham L
      • Symons GF
      • Monif M
      • Shultz SR
      • McDonald SJ.
      The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target.
      TLRs detect DAMPS released by injured cells and upregulate the NLRP3 sensor and IL-1β RNA transcription through nuclear factor-κB (NF-kB) signaling.
      • Govindarajan V
      • de Rivero Vaccari JP
      • Keane RW.
      Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets.
      In addition, changes to the intracellular environment such as K+ efflux and ROS, as well as ionic changes like Cl, activate the inflammasome.
      • O'Brien WT
      • Pham L
      • Symons GF
      • Monif M
      • Shultz SR
      • McDonald SJ.
      The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target.
      However, although the NLRP3 inflammasome has been shown to play a major role in TBI pathology, it is not the only inflammasome that contributes to the innate immune inflammasome response after TBI. For example, the AIM2 and the NLRP1 inflammasome are also activated following TBI.
      • de Rivero Vaccari JP
      • Lotocki G
      • Alonso OF
      • Bramlett HM
      • Dietrich WD
      • Keane RW.
      Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury.
      ,
      • Adamczak SE
      • de Rivero Vaccari JP
      • Dale G
      • et al.
      Pyroptotic neuronal cell death mediated by the AIM2 inflammasome.
      ,
      • Kerr N
      • Lee SW
      • Perez-Barcena J
      • et al.
      Inflammasome proteins as biomarkers of traumatic brain injury.
      Inflammasome proteins are released into the blood and CSF following TBI and these circulating inflammasome proteins are reliable biomarkers for determining injury severity and probable pathological outcomes after TBI.
      • Johnson NH
      • Hadad R
      • Taylor RR
      • et al.
      Inflammatory biomarkers of traumatic brain injury.
      ,
      • Kerr N
      • Lee SW
      • Perez-Barcena J
      • et al.
      Inflammasome proteins as biomarkers of traumatic brain injury.
      ,
      • Perez-Barcena J
      • Rodriguez Pilar J
      • Salazar O
      • et al.
      Serum caspase-1 as an independent prognostic factor in traumatic brain injured patients.
      For instance, Adamczak et al observed increased ASC, caspase-1, and NLRP1 in the CSF of moderate and severe TBI patients, respective amounts correlated with 5-month Glasgow Outcome Scale scores, and elevated protein levels were associated with worsened outcomes.
      • Adamczak S
      • Dale G
      • de Rivero Vaccari JP
      • Bullock MR
      • Dietrich WD
      • Keane RW.
      Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article.
      Kerr and colleagues identified that in human TBI patients, blood serum taken at 1 and 2 days post injury showed levels of ASC and caspase-1 that were elevated after injury, and that increased ASC levels were associated with worsened pathological outcomes.
      • Kerr N
      • Lee SW
      • Perez-Barcena J
      • et al.
      Inflammasome proteins as biomarkers of traumatic brain injury.
      In support of these findings, Pérez‑Bárcena et al determined that blood serum levels of caspase-1 taken at 24 hours after hospital admission for TBI reliably predict pathological outcomes 6 months later with increased caspase-1 levels associated with more severe injury and worsened pathological outcomes.
      • Perez-Barcena J
      • Rodriguez Pilar J
      • Salazar O
      • et al.
      Serum caspase-1 as an independent prognostic factor in traumatic brain injured patients.
      In a previous study, they also observed that caspase-1 levels were elevated in the CSF of TBI patients with increased intracranial pressure, and that increased levels within the CSF were also associated with worsened pathological outcomes.
      • Perez-Barcena J
      • Crespi C
      • Frontera G
      • et al.
      Levels of caspase-1 in cerebrospinal fluid of patients with traumatic brain injury: correlation with intracranial pressure and outcome.
      In addition, Johnson et al observed that increased caspase-1 and IL-10 in the blood serum of TBI patients collected between 1 and 12 hours was associated with worsened outcomes after TBI, and that IL-13 levels could be used to determine injury severity.
      • Johnson NH
      • Hadad R
      • Taylor RR
      • et al.
      Inflammatory biomarkers of traumatic brain injury.
      Moreover, in a murine model of TBI, Lee et al showed that NLRP3, ASC, caspase-1, and IL-1β were all significantly increased within tissue of the injured cerebral cortex at 24 and 48 hours after penetrating injury, and that this was accompanied by increased GSDMD expression and ASC speck oligomerization.
      • Lee SW
      • Gajavelli S
      • Spurlock MS
      • et al.
      Microglial inflammasome activation in penetrating ballistic-like brain injury.
      These results not only indicate that the NLRP3 inflammasome was activated after trauma, but that it also resulted in increased pyroptotic activity and subsequent cytokine release. Interestingly, IL-18 was also seen to be increased at 48 hours post injury and continued to be increased as late as 72 hours post injury.
      • Lee SW
      • Gajavelli S
      • Spurlock MS
      • et al.
      Microglial inflammasome activation in penetrating ballistic-like brain injury.
      The majority of PAMP and DAMP expression after TBI is evident within the first minutes to hours after injury, whereas the activation of microglia and the infiltration of immune cells into the injured tissue occurs later after TBI, primarily within the first few days to a week.
      • Alam A
      • Thelin EP
      • Tajsic T
      • et al.
      Cellular infiltration in traumatic brain injury.
      ,
      • Jarrahi A
      • Braun M
      • Ahluwalia M
      • et al.
      Revisiting traumatic brain injury: from molecular mechanisms to therapeutic interventions.
      As microglia become more activated, the levels of cellular ASC increase,
      • Lee SW
      • de Rivero Vaccari JP
      • Truettner JS
      • Dietrich WD
      • Keane RW.
      The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.
      ,
      • Lee SW
      • Gajavelli S
      • Spurlock MS
      • et al.
      Microglial inflammasome activation in penetrating ballistic-like brain injury.
      thus supporting the idea that microglia are major contributors to inflammasome activity after primary injury. Indeed, TBI studies investigating the effectiveness of reducing microglia activity via chemical inhibition and replacement have observed subsequent reductions in inflammatory activity and brain injury.
      • Bolte AC
      • Lukens JR.
      Neuroimmune cleanup crews in brain injury.
      Although the most deleterious impacts of primary and secondary injury are seen within the first week after injury, continuous deleterious inflammation continues well past the traditional convalescent period.
      • Alam A
      • Thelin EP
      • Tajsic T
      • et al.
      Cellular infiltration in traumatic brain injury.
      ,
      • Jarrahi A
      • Braun M
      • Ahluwalia M
      • et al.
      Revisiting traumatic brain injury: from molecular mechanisms to therapeutic interventions.
      Chronic loss of learning and memory functionality and changes to personality and overall mental health have been observed in patients after TBI.
      • Afsar M
      • Shukla D
      • Bhaskarapillai B
      • Rajeswaran J.
      Cognitive retraining in traumatic brain injury: experience from tertiary care center in southern India.
      Pathophysiologically, chronically activated microglia, autoimmunity, and inflammation are present months to years after the initial injury.
      • Bolte AC
      • Lukens JR.
      Neuroimmune cleanup crews in brain injury.
      ,
      • Jarrahi A
      • Braun M
      • Ahluwalia M
      • et al.
      Revisiting traumatic brain injury: from molecular mechanisms to therapeutic interventions.
      Therefore, TBI is considered a risk factor for numerous CNS disorders including dementia-like disorders such as AD.

      Hallmarks and pathophysiology of AD

      AD, like many neurological and psychiatric disorders, involves a combination of genetic predisposition and environmental/lifestyle triggers that orchestrate the pathological onset and development of the disease.
      • Arenaza-Urquijo EM
      • Vemuri P.
      Resistance vs resilience to Alzheimer disease: clarifying terminology for preclinical studies.
      Increasing numbers of genetic mutations have been linked to AD pathological development. However, alterations to the genes amyloid precursor protein (APP), presenilin (PSEN1, PSEN2), and ApoE (ApoE4) are among the most widely reported, which alter normal protein functionality resulting in the development of the hallmarks of AD pathology.
      • O'Brien RJ
      • Wong PC.
      Amyloid precursor protein processing and Alzheimer's disease.
      ,
      • de Rojas I
      • Moreno-Grau S
      • Tesi N
      • et al.
      Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
      The Aβ plaque is a primary hallmark of AD and results from an alternative method of amyloid precursor protein (APP) cleavage and subsequent oligomerization of the released non-soluble product.
      • Panza F
      • Lozupone M
      • Logroscino G
      • Imbimbo BP.
      A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease.
      APP is a transmembrane protein which is typically cleaved by α-secretase. However, in AD, APP is cleaved by β-secretase (BACE) and then released via γ-secretase as a longer, stickier peptide between 40 to 44 amino acids long, that aggregates to form neurotoxic plaques.
      • O'Brien RJ
      • Wong PC.
      Amyloid precursor protein processing and Alzheimer's disease.
      ,
      • Panza F
      • Lozupone M
      • Logroscino G
      • Imbimbo BP.
      A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease.
      ,
      • Lee S
      • Cho HJ
      • Ryu JH.
      Innate immunity and cell death in Alzheimer's disease.
      Moreover, this description of Aβ plaque formation is overly simplified because other products of APP are generated by cleavage through caspases and other secretases into soluble forms that mediate other physiological functions.
      • Delport A
      • Hewer R.
      The amyloid precursor protein: a converging point in Alzheimer’s disease.
      Although the physiological role of APP in the healthy CNS environment is still not fully understood, studies suggest that it may play a role in cell growth, motility, and survival.
      • O'Brien RJ
      • Wong PC.
      Amyloid precursor protein processing and Alzheimer's disease.
      Interestingly, some studies have suggested that Aβ in its monomeric form may be neuroprotective and found in those individuals without AD symptomology.
      • Giuffrida ML
      • Caraci F
      • Pignataro B
      • et al.
      Beta-amyloid monomers are neuroprotective.
      In pathological AD, however, the insoluble Aβ plaques are deleterious, resulting in CNS cell death, microglia and astrocyte activation, and inflammation. Damage to healthy neurons has been attributed to Aβ disruption of cellular homeostasis, resulting in increased levels of intracellular calcium, increased synaptic glutamate release, and increased excitatory activity in neurons which is in turn compensated by an increase in long term depression and a reduction in post-synaptic glutamate receptors.
      • Zhou Y
      • Sun Y
      • Ma QH
      • Liu Y.
      Alzheimer's disease: amyloid-based pathogenesis and potential therapies.
      Furthermore, Aβ plaques also affect intracellular potassium levels through the disruption of potassium channels and the increased expression and activation of voltage gated potassium channels.
      • Venegas C
      • Heneka MT.
      Inflammasome-mediated innateimmunity in Alzheimer's disease.
      Although Aβ has been the focus of many studies of AD, it does not adequately parallel the pathological properties of AD pathology progression.
      • Panza F
      • Lozupone M
      • Logroscino G
      • Imbimbo BP.
      A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease.
      ,
      • Delport A
      • Hewer R.
      The amyloid precursor protein: a converging point in Alzheimer’s disease.
      pTau tangles are considered another key hallmark of AD pathology and have been shown to elicit a deleterious response within the CNS similar to Aβ. In the healthy CNS, tau serves as a cytoskeletal protein and is utilized in the construction of microtubules, the growth of neurons, potential maintenance of DNA, and axonal transport.
      • Wang Y
      • Mandelkow E.
      Tau in physiology and pathology.
      ,
      • Johnson GV
      • Stoothoff WH.
      Tau phosphorylation in neuronal cell function and dysfunction.
      Tau is expressed via the microtubule associated protein tau (MAPT) gene and is found primarily within neurons but is also present in glia and extracellularly in small amounts.
      • Wang Y
      • Mandelkow E.
      Tau in physiology and pathology.
      Tau has multiple isoforms and tau phosphorylation plays a role in maintaining healthy function and development of the CNS.
      • Johnson GV
      • Stoothoff WH.
      Tau phosphorylation in neuronal cell function and dysfunction.
      Mutations to the MAPT gene and other environmental factors are linked to increases in Tau isoforms that are more susceptible to hyperphosphorylation and other tau pathologies such as frontotemporal dementia.
      • Wang Y
      • Mandelkow E.
      Tau in physiology and pathology.
      ,
      • Johnson GV
      • Stoothoff WH.
      Tau phosphorylation in neuronal cell function and dysfunction.
      In the disease state, tau does not adequately maintain DNA within the cell nucleus, contributing to cell damage, and tau hyperphosphorylation results in microtubule destruction and migration of pTau to the presynaptic terminal, causing dysfunction, vesicle release reductions, and loss of synapse and dendrites.
      • Wang Y
      • Mandelkow E.
      Tau in physiology and pathology.
      In AD, the hyperphosphorylation of Tau makes it less efficient in binding to microtubule associated proteins and instead self-aggregates, forming pTau tangles.
      • Johnson GV
      • Stoothoff WH.
      Tau phosphorylation in neuronal cell function and dysfunction.
      Thus, Aβ plaques and pTau tangles form the pathological hallmarks of AD and elicit damage to the cells of the CNS through the disruption of ionic and cytoskeletal homeostasis, activation of microglia, and induction of inflammation, leading to subsequent cell death.

      Altered microglia in AD

      Microglia play an important role in the pathology of AD through the recognition and clearance of AD-associated DAMPs and subsequent inflammatory activity. Oligomerized Aβ is detected by the surface antigen receptors of microglia and astrocytes as a DAMP.
      • Heneka MT
      • Carson MJ
      • El Khoury J
      • et al.
      Neuroinflammation in Alzheimer's disease.
      ,
      • Rajesh Y
      • Kanneganti T-D.
      Innate Immune Cell Death in Neuroinflammation and Alzheimer’s disease.
      Microglia scavenger receptors identify and mediate Aβ uptake, resulting in microglia activation and inflammatory cytokine release.
      • Venegas C
      • Heneka MT.
      Inflammasome-mediated innateimmunity in Alzheimer's disease.
      About 25% of genes associated with immunity alterations in AD are associated with microglia.
      • Rajesh Y
      • Kanneganti T-D.
      Innate Immune Cell Death in Neuroinflammation and Alzheimer’s disease.
      Genetic mutations, such as PSEN and TREM2 are thought to cause microglia to become dysfunctional, impacting microglial autophagy and lysosomal function.
      • Heneka MT
      • Carson MJ
      • El Khoury J
      • et al.
      Neuroinflammation in Alzheimer's disease.
      ,
      • Orr ME
      • Oddo S.
      Autophagic/lysosomal dysfunction in Alzheimer's disease.
      Interestingly, recent evidence suggests that a new type of microglia known as disease associated microglia (DAM) may be upregulated by AD-associated genes such as TREM2 and ApoE as well as by downregulation of genes associated with microglia homeostasis.
      • Keren-Shaul H
      • Spinrad A
      • Weiner A
      • et al.
      A unique microglia type associated with restricting development of Alzheimer's disease.
      • Ennerfelt HE
      • Lukens JR.
      The role of innate immunity in Alzheimer's disease.
      • Wang H.
      Microglia heterogeneity in Alzheimer's disease: insights from single-cell technologies.
      DAM also show altered autophagy activity, and are present in regions close to Aβ plaques and contain Aβ intracellularly in murine and human samples.
      • Wang H.
      Microglia heterogeneity in Alzheimer's disease: insights from single-cell technologies.
      In addition, PSEN and TREM2 genetic alterations may increase DAM autophagy activity to increase phagocytotic clearance of Aβ plaques.
      • Wang H.
      Microglia heterogeneity in Alzheimer's disease: insights from single-cell technologies.
      ,
      • Deczkowska A
      • Keren-Shaul H
      • Weiner A
      • Colonna M
      • Schwartz M
      • Amit I.
      Disease-associated microglia: a universal immune sensor of neurodegeneration.
      DAM may contribute to AD pathology through the excessive pruning of healthy dendrites and by becoming “frozen” in an activated state in order to increase inflammatory cytokine expression, resulting in a self-driving and perpetually continuous loop of inflammatory activity.
      • Heneka MT
      • Carson MJ
      • El Khoury J
      • et al.
      Neuroinflammation in Alzheimer's disease.
      ,
      • Ennerfelt HE
      • Lukens JR.
      The role of innate immunity in Alzheimer's disease.
      ,
      • Wang H.
      Microglia heterogeneity in Alzheimer's disease: insights from single-cell technologies.
      Additionally, PSEN mutations may contribute to a loss of microglia lysosomal functionality in non-DAM, reducing the capacity of microglia to break down oligomerized Aβ that results in reduced Aβ clearance and increased inflammasome activation.
      • Hemonnot AL
      • Hua J
      • Ulmann L
      • Hirbec H.
      Microglia in Alzheimer disease: well-known targets and new opportunities.
      Studies in murine models have implicated that microglia may also transport Aβ to unaffected regions of the CNS, thus increasing inflammatory activity and overall AD pathology.
      • d'Errico P
      • Ziegler-Waldkirch S
      • Aires V
      • et al.
      Microglia contribute to the propagation of Abeta into unaffected brain tissue.

      Inflammasome and AD interactions

      The inflammasome has emerged in recent years as a key player in a number of CNS diseases and conditions, particularly AD. As noted, Aβ alters the cellular ionic balance in neurons, but acts as a DAMP in microglia and astrocytes (Fig 3).
      • Rajesh Y
      • Kanneganti T-D.
      Innate Immune Cell Death in Neuroinflammation and Alzheimer’s disease.
      ,
      • Venegas C
      • Heneka MT.
      Inflammasome-mediated innateimmunity in Alzheimer's disease.
      ,
      • Zhou Y
      • Sun Y
      • Ma QH
      • Liu Y.
      Alzheimer's disease: amyloid-based pathogenesis and potential therapies.
      Microglia attempt to clear Aβ by phagocytosis. However, in AD, Aβ endocytosis does not result in proper degradation by lysosomes, resulting in numerous alterations of microglia morphology and functionality. Aβ aggregates are crystalline in nature, and once endocytosed, they trigger NLRP3 inflammasome activation, resulting in lysosomal damage and potassium efflux.
      • Venegas C
      • Heneka MT.
      Inflammasome-mediated innateimmunity in Alzheimer's disease.
      ,
      • Lee S
      • Cho HJ
      • Ryu JH.
      Innate immunity and cell death in Alzheimer's disease.
      NLRP3 activation leads to formation of the inflammasome and release of cytokines, inducing oligomerization of ASC into ASC specks. Importantly, ASC specks may act as “seeds” to encourage further polymerization of Aβ that form ASC/Aβ aggregates, which are highly toxic to neurons.
      • Venegas C
      • Kumar S
      • Franklin BS
      • et al.
      Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer's disease.
      ,
      • Venegas C
      • Heneka MT.
      Inflammasome-mediated innateimmunity in Alzheimer's disease.
      Moreover, Aβ and ASC interactions increase NLRP3 activity, and Aβ/ASC aggregates hinder Aβ clearance, but also induce microglial pyroptosis.
      • Friker LL
      • Scheiblich H
      • Hochheiser IV
      • et al.
      beta-amyloid clustering around ASC fibrils boosts its toxicity in microglia.
      These events result in heightened microglial inflammatory activity and release of inflammatory cytokines, thereby inducing pyroptosis and accumulation of ASC and Aβ into the extracellular space that perpetuates inflammation by inducing inflammasome activation and pyroptosis in neighboring CNS cells and microglia.
      • Lee S
      • Cho HJ
      • Ryu JH.
      Innate immunity and cell death in Alzheimer's disease.
      ,
      • Friker LL
      • Scheiblich H
      • Hochheiser IV
      • et al.
      beta-amyloid clustering around ASC fibrils boosts its toxicity in microglia.
      Additionally, murine studies observe that inflammatory cytokines such as IL-1β hamper the clearance activities of microglia, potentially reducing Aβ clearance and the removal of other cellular debris by microglia.
      • Heneka MT
      • Kummer MP
      • Stutz A
      • et al.
      NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
      Furthermore, IL-18 appears to increase BACE activity and alter the processing of APP, potentially increasing production of Aβ.
      • Sutinen EM
      • Pirttila T
      • Anderson G
      • Salminen A
      • Ojala JO.
      Pro-inflammatory interleukin-18 increases Alzheimer's disease-associated amyloid-beta production in human neuron-like cells.
      Fig 3
      Fig 3TBI effects and inflammasome activation linked to AD pathology. TBI and AD are unique pathologies of the CNS, resulting in damage to CNS structures, homeostatic disturbances, and cognitive decline. The inflammasome is seen activated in both pathologies and represents a potential link between the 2 pathologies (black lines), allowing for one to potentially exacerbate the other. In TBI, (pink lines) the inflammasome is activated by DAMPs released by injured and dead cells, while in AD (green lines) the inflammasome is activated by oligomerized Aβ, resulting from BACE cleavage of APP. In both pathologies, the respective proteins are recognized by microglia and astrocytes, which become activated and secrete inflammatory cytokines matured through inflammasome formation. Cytokine release results in pyroptotic activity in neighboring cells and successive release of additional DAMPs, excitatory proteins, ASC specks, and inflammatory cytokines, inducing the inflammatory cascade. Additionally, AD pathology is potentially exacerbated by TBI inflammasome activation through IL-18-induced increased BACE activity, ASC speck interactions with Aβ, and increased pTau formation.
      In addition, pTau has been shown to induce inflammasome activity. Studies in murine models of AD demonstrate that reduction of NLRP3 activity may lead to a reduction in the formation of pTau and pTau tangles.
      • Ising C
      • Venegas C
      • Zhang S
      • et al.
      NLRP3 inflammasome activation drives tau pathology.
      On the other hand, murine models have also shown that pTau activates NLRP3 in microglia and that tau pathology is reduced in ASC knockout mice.
      • Stancu IC
      • Cremers N
      • Vanrusselt H
      • et al.
      Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo.
      Interestingly, Aβ deposition appears to precede tau pathology in AD, suggesting that pTau deposition may represent a downstream product of Aβ pathology.
      • Ising C
      • Venegas C
      • Zhang S
      • et al.
      NLRP3 inflammasome activation drives tau pathology.
      ,
      • Wang H.
      Microglia heterogeneity in Alzheimer's disease: insights from single-cell technologies.
      Indeed, microglia and astrocytic activation, potentially from Aβ or other sources, is thought to encourage pTau formation through the release of inflammatory cytokines such as the inflammasome product IL-1β.
      • Rajesh Y
      • Kanneganti T-D.
      Innate Immune Cell Death in Neuroinflammation and Alzheimer’s disease.
      However, tau pathologies occur in human AD that are separate of Aβ, and human imaging and postmortem studies have demonstrated alterations in microglial inflammatory activity in patients with tau pathology without the presence of Aβ.
      • Stancu IC
      • Cremers N
      • Vanrusselt H
      • et al.
      Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo.
      Lastly, it should be noted that other inflammasomes beside NLRP3 have been implicated to play a role in AD. A recent study found that NLRP1 knockout in AD mouse models resulted in reduced Aβ plaque load, normalized hippocampal dendritic spines, and resulted in improved spatial and episodic memory testing performance.
      • Flores J
      • Noel A
      • Fillion ML
      • LeBlanc AC.
      Therapeutic potential of Nlrp1 inflammasome, Caspase-1, or Caspase-6 against Alzheimer disease cognitive impairment.
      Increased NLRC4 expression and decreased learning and memory functionality was observed in a rat model simulating AD like pathology utilizing streptozotocin injections.
      • Saadi M
      • Karkhah A
      • Pourabdolhossein F
      • Ataie A
      • Monif M
      • Nouri HR.
      Involvement of NLRC4 inflammasome through caspase-1 and IL-1beta augments neuroinflammation and contributes to memory impairment in an experimental model of Alzheimer's like disease.
      AIM2 knock out in murine models was associated with decreased Aβ load and reduced microglia activity, but not with improvements in memory function.
      • Heneka MT
      • McManus RM
      • Latz E.
      Inflammasome signalling in brain function and neurodegenerative disease.
      Taken together, these findings indicate that several inflammasomes contribute to the inflammatory response present in AD.

      TBI as an AD risk factor

      AD is a chronic neurodegenerative disorder, and like TBI, AD is known for structural damage, neuronal loss, chronic inflammation, and behavioral abnormalities. As such, the shared aspects, and potential interactions between these 2 pathologies (Fig 3) are of paramount interest, as trauma could potentially be the pathological facilitator to AD onset in the AD predisposed brain. This is especially true as studies suggest that TBI can lead to the earlier onset of AD pathology in as much as 4 to10 years earlier than the traditional onset.
      • Van Den Heuvel C
      • Thornton E
      • Vink R
      Traumatic brain injury and Alzheimer's disease: a review.
      ,
      • Mohamed AZ
      • Nestor PJ
      • Cumming P
      • Nasrallah FA
      Alzheimer's Disease Neuroimaging I. Traumatic brain injury fast-forwards Alzheimer's pathology: evidence from amyloid positron emission tomorgraphy imaging.
      The effects of trauma on the CNS are interesting when considering that they induce similar disruptions to cellular homeostasis, microglia and astrocyte activation, and inflammatory activity that is seen in AD pathology. For instance, NLRP1, NLRP3, AIM2, ASC speck activity, inflammatory cytokine release, pyroptosis, chronic microglia activation, and neuronal damage have all been observed after TBI in numerous studies and experimental models.
      • Lee SW
      • de Rivero Vaccari JP
      • Truettner JS
      • Dietrich WD
      • Keane RW.
      The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.
      ,
      • Heneka MT
      • McManus RM
      • Latz E.
      Inflammasome signalling in brain function and neurodegenerative disease.
      ,
      • Lee SW
      • Gajavelli S
      • Spurlock MS
      • et al.
      Microglial inflammasome activation in penetrating ballistic-like brain injury.
      ,
      • de Rivero Vaccari JP
      • Lotocki G
      • Alonso OF
      • Bramlett HM
      • Dietrich WD
      • Keane RW.
      Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury.
      ,
      • Kerr N
      • Lee SW
      • Perez-Barcena J
      • et al.
      Inflammasome proteins as biomarkers of traumatic brain injury.
      Likewise, similar observations have been observed in and are thought to contribute to the progression of AD pathology.
      • Venegas C
      • Kumar S
      • Franklin BS
      • et al.
      Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer's disease.
      ,
      • Venegas C
      • Heneka MT.
      Inflammasome-mediated innateimmunity in Alzheimer's disease.
      ,
      • Ennerfelt HE
      • Lukens JR.
      The role of innate immunity in Alzheimer's disease.
      ,
      • Heneka MT
      • Kummer MP
      • Stutz A
      • et al.
      NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
      Experiments involving TBI have observed increased levels of AD-associated proteins after injury, and human observations suggest that about 30% of TBI patients develop Aβ after injury.
      • Kokiko-Cochran ON
      • Godbout JP.
      The inflammatory continuum of traumatic brain injury and alzheimer's disease.
      ,
      • Tran HT
      • LaFerla FM
      • Holtzman DM
      • Brody DL.
      Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities.
      In addition, TBI induced reductions to CNS glymphatic/lymphatic functionality have been shown to reduce Aβ and tau clearance and increase microglia in murine AD models.
      • Frederick NM
      • Tavares GA
      • Louveau A.
      Neuroimmune signaling at the brain borders.
      ,
      • Bolte AC
      • Lukens JR.
      Neuroimmune cleanup crews in brain injury.
      Murine model studies of AD in the 3XTg model have seen increased Aβ levels within 24 hours following TBI, though it should be noted that these levels often returned to sham levels at 7 days after injury
      • Kokiko-Cochran ON
      • Godbout JP.
      The inflammatory continuum of traumatic brain injury and alzheimer's disease.
      (Table Ⅱ).
      Table ⅡTBI outcomes in AD murine models
      AD modelTime post TBIObservationsSources
      3XTg24hIncreased Aβ levels
      • Kokiko-Cochran ON
      • Godbout JP.
      The inflammatory continuum of traumatic brain injury and alzheimer's disease.
      7dSham Aβ levels
      28dIncreased Aβ levels
      • Shishido H
      • Kishimoto Y
      • Kawai N
      • et al.
      Traumatic brain injury accelerates amyloid-beta deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer's disease.
      Decreased spatial memory
      tg-ArcSwe12w and 24wDecreased learning and memory
      • Zysk M
      • Clausen F
      • Aguilar X
      • Sehlin D
      • Syvanen S
      • Erlandsson A
      Long-term effects of traumatic brain injury in a mouse model of Alzheimer's disease.
      Earlier Aβ onset
      R1.403d and 120dIncreased tissue loss
      • Kokiko-Cochran O
      • Ransohoff L
      • Veenstra M
      • et al.
      Altered neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer's disease.
      Inflammatory activity
      APP/PS130d3m: Increased Aβ levels
      • Collins JM
      • King AE
      • Woodhouse A
      • Kirkcaldie MTK
      • Vickers JC.
      Age moderates the effects of traumatic brain injury on beta-amyloid plaque load in APP/PS1 mice.
      6m: Decreased total Aβ, same fibrillar Aβ levels
      8w
      Repeated subclinical blast model.
      Same total Aβ, reduce oligomerized Aβ load
      • Perez Garcia G
      • De Gasperi R
      • Tschiffely AE
      • et al.
      Repetitive low-level blast exposure improves behavioral deficits and chronically lowers Abeta42 in an Alzheimer disease transgenic mouse model.
      Reduced anxiety behavior, improved cognition
      P301S (PS19)1d, 1w, 2m, 6mIncreased Tau aggregation
      • Edwards 3rd, G
      • Zhao J
      • Dash PK
      • Soto C
      • Moreno-Gonzalez I.
      Traumatic brain injury induces tau aggregation and spreading.
      6m: Decreased learning and memory
      Abbreviations: d, days; h, hours; m, months; w, weeks.
      low asterisk Repeated subclinical blast model.
      Shishido and colleagues investigating the 3XTg AD mouse model observed increased Aβ levels within the hippocampus of injured mice 28 days post injury with accompanying decreased spatial memory function
      • Shishido H
      • Kishimoto Y
      • Kawai N
      • et al.
      Traumatic brain injury accelerates amyloid-beta deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer's disease.
      (Table Ⅱ). In a more chronic injury model, Zysk and colleagues observed worsened learning and memory function and evidence of earlier onset of Aβ pathology in tg-ArcSwe AD mice after injury at 12 and 24 weeks post injury when compared to uninjured AD mice.
      • Zysk M
      • Clausen F
      • Aguilar X
      • Sehlin D
      • Syvanen S
      • Erlandsson A
      Long-term effects of traumatic brain injury in a mouse model of Alzheimer's disease.
      In the R1.40 AD mouse model, Kokiko-Cochran and colleagues observed increased tissue loss and continued inflammatory activity after TBI when assessed at 3 and 120 days post injury
      • Kokiko-Cochran O
      • Ransohoff L
      • Veenstra M
      • et al.
      Altered neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer's disease.
      (Table Ⅱ).
      In the APP/PS1 AD mouse model, Collins and colleagues observed increased Aβ levels in the cortex of injured 3-month-old mice. However total Aβ load, though not fibrillar Aβ load, was decreased in mice injured at 6 months of age when compared to uninjured controls at 30 days post-injury.
      • Collins JM
      • King AE
      • Woodhouse A
      • Kirkcaldie MTK
      • Vickers JC.
      Age moderates the effects of traumatic brain injury on beta-amyloid plaque load in APP/PS1 mice.
      Interestingly, opposite results were obtained in a subclinical blast injury model with 20-week-old APP/PS1 mice in which repeated blasts over an 8 week period, 3 times per week, did not reduce overall plaque load but did reduce oligomerized Aβ levels and improved behavioral outcomes.
      • Perez Garcia G
      • De Gasperi R
      • Tschiffely AE
      • et al.
      Repetitive low-level blast exposure improves behavioral deficits and chronically lowers Abeta42 in an Alzheimer disease transgenic mouse model.
      Tau pathology has been identified in as many as 1/3 of TBI patients after single and multiple injuries.
      • Katsumoto A
      • Takeuchi H
      • Tanaka F.
      Tau pathology in chronic traumatic encephalopathy and Alzheimer's disease: similarities and differences.
      Interestingly, a U.S. Department of Defense study led by Clark and colleagues identified increased pTau load in the CSF of Vietnam era veterans who had undergone a TBI but did not see increased Aβ expression.
      • Clark AL
      • Weigand AJ
      • Bangen KJ
      • et al.
      Higher cerebrospinal fluid tau is associated with history of traumatic brain injury and reduced processing speed in Vietnam-era veterans: a Department of Defense Alzheimer's Disease Neuroimaging Initiative (DOD-ADNI) study.
      pTau is also seen in murine models after TBI, and has been demonstrated to be phagocytosed by and able to activate microglia.
      • Katsumoto A
      • Takeuchi H
      • Takahashi K
      • Tanaka F.
      Microglia in Alzheimer's disease: risk factors and inflammation.
      Edwards and colleagues observed increased pTau aggregation after TBI in the P301S Tau mouse model as early as 1 day after injury and noted decreased learning and memory function at 6 months post injury accompanying increased pTau aggregation.
      • Edwards 3rd, G
      • Zhao J
      • Dash PK
      • Soto C
      • Moreno-Gonzalez I.
      Traumatic brain injury induces tau aggregation and spreading.
      Additionally, disruption of the BBB secondary to TBI is also of interest as studies have shown increased plaque formation near areas of BBB damaged due to age.
      • VanItallie TB.
      Alzheimer's disease: innate immunity gone awry?.
      All points considered, TBI represents a potential trigger of AD development through the initiation of neuronal cell death, diffuse axonal injury, BBB disruption, microglia activation, and inflammasome activity, all of which are seen as major drivers of AD pathology and represent current areas of therapeutic research.

      New therapeutic opportunities and current clinical trials

      Numerous studies and potential therapeutic interventions are currently being investigated in order to prevent, reduce, or reverse the effects of TBI and AD pathology. In both conditions, the inflammasome pathway offers attractive therapeutic targets for the reduction of damaging inflammatory secondary injury cascades. These may include the prevention of the priming phase or step 1 through targeting NF-κB, blocking the activity of the inflammasome sensor protein, such as NLRP3, prevention of ASC speck oligomerization, targeting caspase-1 activity, or blockage of GSDMD pyroptotic activity.
      • Zahid A
      • Li B
      • Kombe AJK
      • Jin T
      • Tao J
      Pharmacological Inhibitors of the NLRP3 Inflammasome.
      • Desu HL
      • Plastini M
      • Illiano P
      • et al.
      IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.
      • Place DE
      • Kanneganti TD.
      Metabolic regulation of pyroptotic cell death expands the therapeutic landscape for treating inflammatory disease.
      Therapeutics that target NLRP3 activity such as MCC950 showed initial promising results through the reduction of NLRP3 and microglia activation and increased Aβ phagocytosis in AD, and reduced caspase-1 and IL-1β activity in TBI.
      • Bakhshi S
      • Shamsi S.
      MCC950 in the treatment of NLRP3-mediated inflammatory diseases: latest evidence and therapeutic outcomes.
      Studies with the caspase-1 inhibitor VX-765 have demonstrated reduced inflammatory cytokine and GSDM-D activity in a murine model of TBI, as well as delayed inflammatory onset in an AD murine models though without altering plaque load.
      • Flores J
      • Noel A
      • Foveau B
      • Beauchet O
      • LeBlanc AC.
      Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.
      ,
      • Sun Z
      • Nyanzu M
      • Yang S
      • et al.
      VX765 attenuates pyroptosis and HMGB1/TLR4/NF-kappaB pathways to improve functional outcomes in TBI mice.
      Studies involving an anti-ASC drug called IC100 show exciting results in reducing inflammatory activity and improving functional outcomes in murine models of inflammaging, multiple sclerosis, and CNS injury induced acute lung injury.
      • Kerr NA
      • de Rivero Vaccari JP
      • Abbassi S
      • et al.
      Traumatic brain injury-induced acute lung injury: evidence for activation and inhibition of a neural-respiratory-inflammasome axis.
      ,
      • Cyr B
      • Hadad R
      • Keane RW
      • de Rivero Vaccari JP.
      The role of non-canonical and canonical inflammasomes in inflammaging.
      ,
      • Desu HL
      • Plastini M
      • Illiano P
      • et al.
      IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.
      Additionally, targeting ASC lowered the expression of caspase-1 and reduced pyroptotic cell death in rats after TBI.
      • Lee SW
      • de Rivero Vaccari JP
      • Truettner JS
      • Dietrich WD
      • Keane RW.
      The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.
      Given the unique role of ASC in the inflammasome and its interactions with AD proteins, ASC represents an interesting target in both pathologies, as hindrance of ASC speck activity could reduce plaque progression, inflammasome activation, and reduce inflammatory signaling in both AD and TBI pathologies.
      Beyond the bench, numerous human clinical trials are investigating the effectiveness of targeting the inflammasome in reducing the progression of inflammatory linked pathologies within and outside of the CNS (Table Ⅲ). Due to current research targets, a majority of current inflammasome clinical trials are primarily focused on treating COVID-19 infections and related pathologies such as pneumonia and lung damage.
      Table ⅢRecent clinical trials targeting the inflammasome
      Drug nameInflammasome targetDisorderStudy typeResultsSource
      DFV890NLRP3COVID-19Clinical TrialReduced COVID pathology

      Study of efficacy and safety of DV890 in patients with COVID-19 pneumonia. Available at: https://ClinicalTrials.gov/show/NCT04382053. Accessed June 2022.

      Reduced ventilator intervention
      MAS825NLRC4COVID-19Clinical TrialDecreased C-reactive protein

      Study of efficacy and safety of MAS825 in patients with COVID-19.Available at: https://ClinicalTrials.gov/show/NCT04382651. Accessed June 2022.

      No change in clinical outcomes
      OLT1177NLRP3Heart FailureClinical TrialImproved left ventricular ejection fraction
      • Wohlford GF
      • Van Tassell BW
      • Billingsley HE
      • et al.
      Phase 1B, randomized, double-blinded, dose escalation, single-center, repeat dose safety and pharmacodynamics study of the oral NLRP3 inhibitor dapansutrile in subjects with NYHA II-III systolic heart failure.
      DapansutrileGoutClinical TrialReduced joint pain
      • Kluck V
      • Jansen T
      • Janssen M
      • et al.
      Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial.
      IZD334NLRP3Autoinflammatory DiseaseClinical TrialTrial complete
      • Chauhan D
      • Vande Walle L
      • Lamkanfi M.
      Therapeutic modulation of inflammasome pathways.
      InzomelidNLRP3Autoinflammatory DiseaseClinical TrialTrial complete
      • Chauhan D
      • Vande Walle L
      • Lamkanfi M.
      Therapeutic modulation of inflammasome pathways.
      MCC950NLRP3ADAnimal StudyIncreased Aβ phagocytosis
      • Bakhshi S
      • Shamsi S.
      MCC950 in the treatment of NLRP3-mediated inflammatory diseases: latest evidence and therapeutic outcomes.
      TBIAnimal StudyReduced caspase-1 and IL-1β activity
      • Bakhshi S
      • Shamsi S.
      MCC950 in the treatment of NLRP3-mediated inflammatory diseases: latest evidence and therapeutic outcomes.
      Rheumatoid ArthritisClinical TrialSevere side effects
      • Bakhshi S
      • Shamsi S.
      MCC950 in the treatment of NLRP3-mediated inflammatory diseases: latest evidence and therapeutic outcomes.
      ,
      • Chen QL
      • Yin HR
      • He QY
      • Wang Y.
      Targeting the NLRP3 inflammasome as new therapeutic avenue for inflammatory bowel disease.
      VX765Caspase-1TBIAnimal StudyReduced cytokine and GSDM-D activity
      • Sun Z
      • Nyanzu M
      • Yang S
      • et al.
      VX765 attenuates pyroptosis and HMGB1/TLR4/NF-kappaB pathways to improve functional outcomes in TBI mice.
      Alzheimer's DiseaseAnimal StudyDelayed inflammatory onset
      • Flores J
      • Noel A
      • Foveau B
      • Beauchet O
      • LeBlanc AC.
      Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.
      No change in plaque load
      IC-100ASCAgingAnimal StudyReduced Caspase-1,8, Il-1β, ASC, NLRP-1 expression
      • Cyr B
      • Hadad R
      • Keane RW
      • de Rivero Vaccari JP.
      The role of non-canonical and canonical inflammasomes in inflammaging.
      Multiple SclerosisAnimal StudyReduced T cell, myeloid cell, and microglia activation
      • Desu HL
      • Plastini M
      • Illiano P
      • et al.
      IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.
      CNS induced Lung InjuryAnimal StudyReduced Il-1β, ASC, caspase-1, AIM2 expression
      • Kerr NA
      • de Rivero Vaccari JP
      • Abbassi S
      • et al.
      Traumatic brain injury-induced acute lung injury: evidence for activation and inhibition of a neural-respiratory-inflammasome axis.
      Reduced lung tissue damage
      TBIAnimal StudyReduced caspase-1 and pyroptosis
      • Lee SW
      • de Rivero Vaccari JP
      • Truettner JS
      • Dietrich WD
      • Keane RW.
      The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.
      The inflammasome represents a promising target in the treatment of numerous inflammatory fueled pathologies. Current clinical studies have shown that therapeutics that target inhibition of the inflammasome sensor are safe, well tolerated, and potentially effective in numerous inflammatory pathologies.
      A NLRP3 antagonist known as DFV890 developed by Novartis has just finished a phase 2 clinical trial investigating its effectiveness in treating severe respiratory infections of COVID-19. Provided data suggests that patients who were administered DFV 890 along with standard medical care had no higher chance of dying in the intensive care unit than patients that received standard medical care alone.

      Study of efficacy and safety of DV890 in patients with COVID-19 pneumonia. Available at: https://ClinicalTrials.gov/show/NCT04382053. Accessed June 2022.

      Interestingly, researchers noted that slightly less of the patients that received DFV890 required ventilator intervention and also that slightly more of these patients had reduced COVID-19 pathology.

      Study of efficacy and safety of DV890 in patients with COVID-19 pneumonia. Available at: https://ClinicalTrials.gov/show/NCT04382053. Accessed June 2022.

      Another study, which instead targeted NLRC4 with the drug MAS825 also investigated the effectiveness of inflammasome targeting in treating COVID-19 patients. Results suggest that patients administered MAS825 along with standard of care had decreased levels of the inflammatory biomarker C-reactive protein (CRP) compared to placebo at 15 days post treatment.

      Study of efficacy and safety of MAS825 in patients with COVID-19.Available at: https://ClinicalTrials.gov/show/NCT04382651. Accessed June 2022.

      However, these results did not translate to an improvement in clinical outcomes or reduce the need for other interventions.

      Study of efficacy and safety of MAS825 in patients with COVID-19.Available at: https://ClinicalTrials.gov/show/NCT04382651. Accessed June 2022.

      OLT1177 (dapansutrile), a NLRP3 inhibitor developed by Olatec has undergone a few clinical trials which have shown positive results and is currently being investigated for treating COVID-19 symptoms. In a clinical trial investigating use in systolic heart failure, patients administered dapansutrile 2,000mg had improved left ventricular ejection fraction and exercise time compared to placebo controls at day 14 and was deemed safe for use.
      • Wohlford GF
      • Van Tassell BW
      • Billingsley HE
      • et al.
      Phase 1B, randomized, double-blinded, dose escalation, single-center, repeat dose safety and pharmacodynamics study of the oral NLRP3 inhibitor dapansutrile in subjects with NYHA II-III systolic heart failure.
      When used for the treatment of gout, which is linked to IL-1β expression secondary to NLRP3 activation from monosodium urate crystals, patients administered dapansutrile reported reduced joint pain when compared to controls.
      • Kluck V
      • Jansen T
      • Janssen M
      • et al.
      Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial.
      Additional inhibitors of NLRP3 activity analogous to MCC950, such as IZD334 and Inzomelid developed by Inflazome (Roche) are currently being assessed for safety and clinical effectiveness in autoinflammatory disease trials that have just recently been completed.
      • Chauhan D
      • Vande Walle L
      • Lamkanfi M.
      Therapeutic modulation of inflammasome pathways.
      Although these studies are not investigating CNS pathologies, given how damage to 1 organ system such as the brain and spinal cord has been shown to secondarily impact other organ systems such as the lungs or gut through inflammasome activity, any effective compound in reducing the pathology of one could be potentially effective in reducing the pathology of another.
      • Kerr NA
      • de Rivero Vaccari JP
      • Abbassi S
      • et al.
      Traumatic brain injury-induced acute lung injury: evidence for activation and inhibition of a neural-respiratory-inflammasome axis.
      ,
      • Kerr NA
      • Sanchez J
      • O’Connor G
      • et al.
      Inflammasome-regulated pyroptotic cell death in disruption of the gut-brain axis after stroke.
      As such, attention should be paid to all types of inflammasome clinical trials, and their findings should be considered for potential application to CNS pathologies such as TBI and AD. Additionally, since numerous studies show that inflammasome inhibitors are well tolerated and safe, continued investigation of new targets for inflammasome inhibition are encouraged. Currently, a search of clinicaltrials.gov utilizing the term “inflammasome” returns 45 studies, none of which are or have investigated inflammasome interactions in either TBI or AD pathologies, or combinations of the 2 pathologies. Future studies and drug investigations should consider the role of the inflammasome in CNS pathology, as well as more than just the products of inflammasome maturation, such as IL-1β and IL-18 but also to the individual proteins that are produced in order to build the inflammasome such as ASC specks.

      Conclusion

      The pathologies of TBI and AD are diverse, chronic, and psychologically debilitating for patients. Research of these 2 pathologies is of paramount interest and importance as incidences of both are increasing with the aging population. Emerging evidence has accumulated describes a link between TBI and AD pathologies. Cell injury in the simplest sense is the 1 true linker of AD and TBI, as the products of cell injury are represented in both pathologies. Neuronal injury from trauma or from Aβ and pTau activity result in cell death and the release of DAMPs, excitatory proteins, and disruptions to ionic homeostasis. These disturbances to CNS homeostasis in turn trigger the activation of the innate immune system, microglia, and the inflammasome, resulting in continued inflammatory activity as heightened inflammasome activation induces pyroptotic cell death. In this scenario, heightened inflammation becomes perpetual. In AD, the continued production and lack of Aβ clearance, and pTau activity feeds this inflammatory cycle thereby producing DAMPs and neuronal ionic unbalancing agents to trigger neuronal inflammasome activity and inflammatory astrocytic and microglial activation. This cycle becomes more amplified in AD in which microglia in the AD brain assume a self-perpetuating inflammatory morphology. Additionally, inflammasome products, such as ASC and IL-18 encourage Aβ pathology and in turn induces pTau pathology downstream.
      Taken together, TBI represents a risk factor in AD development by enhancing inflammation and promoting AD pathological onset. Furthermore, the genetic predisposition associated with AD may impact TBI pathological and functional outcomes. TBI can be an inflammatory trigger through tissue damage, astrocyte and microglia activation and therefore it is not surprising that TBI would be considered a risk factor for AD. However, although these pathologies have many similarities, they also have unique signatures. Injury severity and location are major factors in determining the degree of damage and cognitive abnormalities. On the other hand, AD is associated with numerous genetic mutations and potentially can be the result of environmental factors. As such, it should be noted that one does not necessarily always precede the other, and that individual genetic predisposition and environmental factors must be considered when determining overall risk for chronic pathology after CNS injury.
      Given the inconsistent results using murine models of AD, and that numerous AD genetic models and TBI experimental models currently exist, we must be cautious not to overgeneralize observations and extrapolate these results to humans. Regardless, the inflammasome represents a viable target for reducing the impact of each pathology, as well as reducing crosstalk between them. Current results have shown that inflammasome inhibitors appears to be a safe and potentially effective in reducing pathology in TBI and AD, and a wide variety of inflammatory associated disorders such as MS, kidney disease, stroke, lung damage, and aging. Although current clinical trials have focused on inflammasome sensor inhibition, future studies will need to focus on other proteins associated with formation of the inflammasome complex. Given the interactions between ASC and Aβ or IL-18 and BACE in AD, and that numerous inflammasome sensors exist and are implicated in TBI and AD, future clinical studies should consider targeting multiple inflammasome sensors or adaptor molecules. In addition, neuroimmune interactions involving the meningeal lymphatic system at the CNS borders will likely provide information about the immune responses in the CNS; and potentially yield therapeutic strategies to treat neurological disorders, including TBI and AD.
      In conclusion, AD and TBI individually represent complex disorders with numerous factors that play into pathological onset, development, and prognosis. As such, researchers and medical professionals must take into consideration all factors in an experimental study or individual patient's environment in an attempt to evaluate the related pathology holistically. Since genetic predisposition has been implicated as a major factor in AD pathology and could likewise influence TBI pathology, these variables should be taken into consideration along with environmental factors when evaluating potential experimental models and injury methods. As such, while TBI represents a known source of cognitive decline, inflammatory activity, and potential AD protein development, it is not a guaranteed cause of AD. Additionally, while AD predisposition could potentially impact inflammatory activity within the CNS, it does not guarantee AD pathological development with or without TBI. Regardless, the inflammasome represents a shared characteristic of numerous pathologies and a promising target for the development of novel and effective therapeutic interventions. This is especially the case when considering the role of inflammasome-derived cytokines, activated microglia and astrocytes, as well as pyroptotic cell death induced by trauma or AD pathology.

      Acknowledgments

      Conflicts of Interest: JPdRV, HMB, RWK, and WDD are co-founders and managing members of InflamaCORE, LLC and have licensed patents on inflammasome proteins as biomarkers of injury and disease as well as on targeting inflammasome proteins for therapeutic purposes. JPdRV, HMB, RWK, and WDD are Scientific Advisory Board Members of ZyVersa Therapeutics. NHJ declares no conflicts of interest.
      This research was funded by an R01 grant from the NIH/NINDS to RWK and JPdRV ( R01NS113969-01 ), a FDOH grant ( 21A13 ) to WDD and an RF1 grant from the NIH/NINDS/NIA ( 1RF1NS125578-01 ) to WDD and JPdRV.
      We would like to thank Karen Cashmere who assisted with compiling clinical trial data investigating therapeutics targeting the inflammasome. All figures were created with BioRender.com. All authors have read the journal's authorship agreement and that the manuscript has been reviewed by and approved by all named authors.

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