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The NLRP3 inflammasome fires up heme-induced inflammation in hemolytic conditions

  • Suruchi Salgar
    Affiliations
    Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, Texas

    Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, Texas
    Search for articles by this author
  • Beatriz E Bolívar
    Affiliations
    Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, Texas

    Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, Texas

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
    Search for articles by this author
  • Jonathan M Flanagan
    Affiliations
    Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, Texas

    Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, Texas
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  • Shaniqua J Anum
    Affiliations
    Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, Texas

    Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, Texas
    Search for articles by this author
  • Lisa Bouchier-Hayes
    Correspondence
    Reprint requests: Lisa Bouchier-Hayes, Baylor College of Medicine/Texas Children's Hospital, 1102 Bates Ave., FC 1030.08, Houston, TX 77030, USA.
    Affiliations
    Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, Texas

    Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, Texas

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
    Search for articles by this author
Published:August 27, 2022DOI:https://doi.org/10.1016/j.trsl.2022.08.011

      Abstract

      Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1 and release of pro-inflammatory cytokines IL-1β and IL-18. Heme also activates the non-canonical inflammasome pathway, which may contribute to NLRP3 inflammasome formation and leads to pyroptosis, a type of inflammatory cell death. Some clinical studies indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients with sickle cell disease and other hemolytic conditions. However, a thorough understanding of the mechanisms of heme-induced inflammasome activation is needed to fully leverage this pathway for clinical benefit. This review will explore the mechanisms of heme-induced NLRP3 inflammasome activation and the role of this pathway in hemolytic conditions including sickle cell disease.

      Abbreviations:

      ASC (apoptosis-associated speck-like protein containing a CARD), CARD (caspase activation and recruitment domain), DAMP (damage associated molecular pattern), GSDMD (gasdermin D), Hb (hemoglobin), HO-1 (heme oxygenase-1), Hp (haptoglobin), Hpx (hemopexin), IL (interleukin), MD-2 (myeloid differentiation factor-2), Mb (myoglobin), MLKL (mixed lineage kinase domain like pseudokinase), mtROS (mitochondrial reactive oxygen species), NET (neutrophil extracellular trap), NLRP3 (nod-like receptor protein with a PYRIN domain 3), NOX2 (NADPH oxidase-2), PAMP (pathogen associated molecular pattern), PI3K (phosphoinositide 3-kinase), PRR (pattern recognition receptor), SCD (sickle cell disease), Syk (spleen tyrosine kinase), TLR (toll-like receptor), TNFα (tumor necrosis factor alpha), TNFR1 (tumor necrosis factor receptor 1), VCAM-1 (vascular cell adhesion molecule 1)
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      References

        • Bianchi ME.
        DAMPs, PAMPs and alarmins: all we need to know about danger.
        J Leukoc Biol. 2007; 81: 1-5
        • Dutra FF
        • Bozza MT.
        Heme on innate immunity and inflammation.
        Front Pharmacol. 2014; 5: 115
        • Dutra FF
        • Alves LS
        • Rodrigues D
        • et al.
        Hemolysis-induced lethality involves inflammasome activation by heme.
        Proc Natl Acad Sci U S A. 2014; 111: E4110-E4118
        • Bolivar BE
        • Brown-Suedel AN
        • Rohrman BA
        • et al.
        Noncanonical roles of caspase-4 and caspase-5 in heme-driven IL-1beta release and cell death.
        J Immunol. 2021; 206: 1878-1889
        • Bolivar BE
        • Vogel TP
        • Bouchier-Hayes L.
        Inflammatory caspase regulation: maintaining balance between inflammation and cell death in health and disease.
        FEBS J. 2019; 286: 2628-2644
        • Franchi L
        • Eigenbrod T
        • Munoz-Planillo R
        • Nunez G.
        The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis.
        Nat Immunol. 2009; 10: 241-247
        • Wun T
        • Cordoba M
        • Rangaswami A
        • Cheung AW
        • Paglieroni T.
        Activated monocytes and platelet-monocyte aggregates in patients with sickle cell disease.
        Clin Lab Haematol. 2002; 24: 81-88
        • Pitanga TN
        • Oliveira RR
        • Zanette DL
        • et al.
        Sickle red cells as danger signals on proinflammatory gene expression, leukotriene B4 and interleukin-1 beta production in peripheral blood mononuclear cell.
        Cytokine. 2016; 83: 75-84
        • Muller-Eberhard U
        • Javid J
        • Liem HH
        • Hanstein A
        • Hanna M.
        Brief report: plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases.
        Blood. 1968; 32: 811-815
        • Vinchi F
        • Sparla R
        • Passos ST
        • et al.
        Vasculo-toxic and pro-inflammatory action of unbound haemoglobin, haem and iron in transfusion-dependent patients with haemolytic anaemias.
        Br J Haematol. 2021; 193: 637-658
        • Gilles-Gonzalez MA
        • Gonzalez G.
        Heme-based sensors: defining characteristics, recent developments, and regulatory hypotheses.
        J Inorg Biochem. 2005; 99: 1-22
        • Dawson JH.
        Probing structure-function relations in heme-containing oxygenases and peroxidases.
        Science. 1988; 240 (New York, NY): 433-439
        • Mansouri A
        • Lurie AA.
        Concise review: methemoglobinemia.
        Am J Hematol. 1993; 42: 7-12
        • Martins R
        • Knapp S.
        Heme and hemolysis in innate immunity: adding insult to injury.
        Curr Opin Immunol. 2018; 50: 14-20
        • Sadrzadeh SM
        • Graf E
        • Panter SS
        • Hallaway PE
        • Eaton JW.
        Hemoglobin. A biologic fenton reagent.
        J Biol Chem. 1984; 259: 14354-14356
        • Aich A
        • Freundlich M
        • Vekilov PG.
        The free heme concentration in healthy human erythrocytes.
        Blood Cells Mol Dis. 2015; 55: 402-409
        • Donegan RK
        • Moore CM
        • Hanna DA
        • Reddi AR.
        Handling heme: the mechanisms underlying the movement of heme within and between cells.
        Free Radic Biol Med. 2019; 133: 88-100
        • Hopp MT
        • Imhof D.
        Linking labile heme with thrombosis.
        J Clin Med. 2021; 10427
        • Sawicki KT
        • Chang HC
        • Ardehali H.
        Role of heme in cardiovascular physiology and disease.
        J Am Heart Assoc. 2022; 4e001138
        • Rapido F.
        The potential adverse effects of haemolysis.
        Blood Transfus. 2017; 15: 218-221
        • Thomsen JH
        • Etzerodt A
        • Svendsen P
        • Moestrup SK.
        The haptoglobin-CD163-heme oxygenase-1 pathway for hemoglobin scavenging.
        Oxid Med Cell Long. 2013; 2013523652
        • Vallelian F
        • Buehler PW
        • Schaer DJ.
        Hemolysis, free hemoglobin toxicity and scavenger protein therapeutics.
        Blood. 2022; (In press)
        • Bozza MT
        • Jeney V.
        Pro-inflammatory actions of heme and other hemoglobin-derived DAMPs.
        Front Immunol. 2020; 11: 1323
        • Kumar S
        • Bandyopadhyay U.
        Free heme toxicity and its detoxification systems in human.
        Toxicol Lett. 2005; 157: 175-188
        • Schaer DJ
        • Buehler PW
        • Alayash AI
        • Belcher JD
        • Vercellotti GM.
        Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins.
        Blood. 2013; 121: 1276-1284
        • Soares MP
        • Bozza MT.
        Red alert: labile heme is an alarmin.
        Curr Opin Immunol. 2016; 38: 94-100
        • Immenschuh S
        • Vijayan V
        • Janciauskiene S
        • Gueler F
        Heme as a target for therapeutic interventions.
        Front Pharmacol. 2017; 8: 146
        • Takeuchi O
        • Akira S.
        Pattern recognition receptors and inflammation.
        Cell. 2010; 140: 805-820
        • Erdei J
        • Toth A
        • Balogh E
        • et al.
        Induction of NLRP3 inflammasome activation by heme in human endothelial cells.
        Oxid Med Cell Long. 2018; 20184310816
        • Li Q
        • Fu W
        • Yao J
        • et al.
        Heme induces IL-1beta secretion through activating NLRP3 in kidney inflammation.
        Cell Biochem Biophys. 2014; 69: 495-502
        • Swanson KV
        • Deng M
        • Ting JP.
        The NLRP3 inflammasome: molecular activation and regulation to therapeutics.
        Nat Rev Immunol. 2019; 19: 477-489
        • Lu A
        • Wu H.
        Structural mechanisms of inflammasome assembly.
        FEBS J. 2015; 282: 435-444
        • Schroder K
        • Tschopp J.
        The inflammasomes.
        Cell. 2010; 140: 821-832
        • Malik A
        • Kanneganti TD.
        Inflammasome activation and assembly at a glance.
        J Cell Sci. 2017; 130: 3955-3963
        • Gabay C
        • Lamacchia C
        • Palmer G.
        IL-1 pathways in inflammation and human diseases.
        Nat Rev Rheumatol. 2010; 6: 232-241
        • Yasuda K
        • Nakanishi K
        • Tsutsui H.
        Interleukin-18 in health and disease.
        Int J Mol Sci. 2019; 20649
        • Shi J
        • Zhao Y
        • Wang K
        • et al.
        Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.
        Nature. 2015; 526: 660-665
        • He WT
        • Wan H
        • Hu L
        • et al.
        Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion.
        Cell Res. 2015; 25: 1285-1298
        • Figueiredo RT
        • Fernandez PL
        • Mourao-Sa DS
        • et al.
        Characterization of heme as activator of Toll-like receptor 4.
        J Biol Chem. 2007; 282: 20221-20229
        • Vaure C
        • Liu Y.
        A comparative review of toll-like receptor 4 expression and functionality in different animal species.
        Front Immunol. 2014; 5: 316
        • Zhang P
        • Nguyen J
        • Abdulla F
        • et al.
        Soluble MD-2 and heme in sickle cell disease plasma promote pro-inflammatory signaling in endothelial cells.
        Front Immunol. 2021; 12632709
        • Belcher JD
        • Zhang P
        • Nguyen J
        • et al.
        Identification of a heme activation site on the MD-2/TLR4 complex.
        Front Immunol. 2020; 11: 1370
        • Park BS
        • Song DH
        • Kim HM
        • Choi BS
        • Lee H
        • Lee JO.
        The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.
        Nature. 2009; 458: 1191-1195
        • May O
        • Yatime L
        • Merle NS
        • et al.
        The receptor for advanced glycation end products is a sensor for cell-free heme.
        FEBS J. 2021; 288: 3448-3464
        • Mulrennan S
        • Baltic S
        • Aggarwal S
        • et al.
        The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes.
        Sci Rep. 2015; 5: 8931
        • Morbini P
        • Villa C
        • Campo I
        • Zorzetto M
        • Inghilleri S
        • Luisetti M.
        The receptor for advanced glycation end products and its ligands: a new inflammatory pathway in lung disease?.
        Mod Pathol. 2006; 19: 1437-1445
        • Wang S
        • Song R
        • Wang Z
        • Jing Z
        • Wang S
        • Ma J.
        S100A8/A9 in inflammation.
        Front Immunol. 2018; 9: 1298
        • Silveira AAA
        • Mahon OR
        • Cunningham CC
        • et al.
        S100A8 acts as an autocrine priming signal for heme-induced human Mvarphi pro-inflammatory responses in hemolytic inflammation.
        J Leukoc Biol. 2019; 106: 35-43
        • Mocsai A
        • Ruland J
        • Tybulewicz VL.
        The SYK tyrosine kinase: a crucial player in diverse biological functions.
        Nat Rev Immunol. 2010; 10: 387-402
        • Belambri SA
        • Rolas L
        • Raad H
        • Hurtado-Nedelec M
        • Dang PM
        • El-Benna J.
        NADPH oxidase activation in neutrophils: role of the phosphorylation of its subunits.
        Eur J Clin Invest. 2018; 48 (Suppl): e12951
        • Hennige AM
        • Lembert N
        • Wahl MA
        Ammon HP. Oxidative stress increases potassium efflux from pancreatic islets by depletion of intracellular calcium stores.
        Free Radic Res. 2000; 33: 507-516
        • Korolnek T
        • Hamza I.
        Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism.
        Front Pharmacol. 2014; 5: 126
        • Chiabrando D
        • Vinchi F
        • Fiorito V
        • Mercurio S
        • Tolosano E.
        Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes.
        Front Pharmacol. 2014; 5: 61
        • Le Blanc S
        • Garrick MD
        • Arredondo M
        Heme carrier protein 1 transports heme and is involved in heme-Fe metabolism.
        Am J Physiol Cell Physiol. 2012; 302: C1780-C1785
        • Kajiwara Y
        • Schiff T
        • Voloudakis G
        • et al.
        A critical role for human caspase-4 in endotoxin sensitivity.
        J Immunol. 2014; 193: 335-343
        • Shi J
        • Zhao Y
        • Wang Y
        • et al.
        Inflammatory caspases are innate immune receptors for intracellular LPS.
        Nature. 2014; 514: 187-192
        • Casson CN
        • Yu J
        • Reyes VM
        • et al.
        Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens.
        Proc Natl Acad Sci U S A. 2015; 112: 6688-6693
        • Schmid-Burgk JL
        • Gaidt MM
        • Schmidt T
        • Ebert TS
        • Bartok E
        • Hornung V.
        Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells.
        Eur J Immunol. 2015; 45: 2911-2917
        • Kayagaki N
        • Stowe IB
        • Lee BL
        • et al.
        Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.
        Nature. 2015; 526: 666-671
        • Kamens J
        • Paskind M
        • Hugunin M
        • et al.
        Identification and characterization of ICH-2, a novel member of the interleukin-1 beta-converting enzyme family of cysteine proteases.
        J Biol Chem. 1995; 270: 15250-15256
        • Kayagaki N
        • Warming S
        • Lamkanfi M
        • et al.
        Non-canonical inflammasome activation targets caspase-11.
        Nature. 2011; 479: 117-121
        • Baker PJ
        • Boucher D
        • Bierschenk D
        • et al.
        NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5.
        Eur J Immunol. 2015; 45: 2918-2926
        • Evavold CL
        • Ruan J
        • Tan Y
        • Xia S
        • Wu H
        • Kagan JC.
        The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages.
        Immunity. 2018; 48: 35-44 e6
        • Fortes GB
        • Alves LS
        • de Oliveira R
        • et al.
        Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production.
        Blood. 2012; 119: 2368-2375
        • Newton K.
        RIPK1 and RIPK3: critical regulators of inflammation and cell death.
        Trends Cell Biol. 2015; 25: 347-353
        • Vandenabeele P
        • Galluzzi L
        • Vanden Berghe T
        • Kroemer G
        Molecular mechanisms of necroptosis: an ordered cellular explosion.
        Nat Rev Mol Cell Biol. 2010; 11: 700-714
        • Dixon SJ
        • Lemberg KM
        • Lamprecht MR
        • et al.
        Ferroptosis: an iron-dependent form of nonapoptotic cell death.
        Cell. 2012; 149: 1060-1072
        • NaveenKumar SK
        • SharathBabu BN
        • Hemshekhar M
        • Kemparaju K
        • Girish KS
        • Mugesh G.
        The role of reactive oxygen species and ferroptosis in heme-mediated activation of human platelets.
        ACS Chem Biol. 2018; 13: 1996-2002
        • Solle M
        • Labasi J
        • Perregaux DG
        • et al.
        Altered cytokine production in mice lacking P2X(7) receptors.
        J Biol Chem. 2001; 276: 125-132
        • Xu H
        • Sun Y
        • Zhang Y
        • et al.
        Protoporphyrin IX induces a necrotic cell death in human THP-1 macrophages through activation of reactive oxygen species/c-Jun N-terminal protein kinase pathway and opening of mitochondrial permeability transition pore.
        Cell Physiol Biochem. 2014; 34: 1835-1848
        • Liu X
        • Spolarics Z.
        Methemoglobin is a potent activator of endothelial cells by stimulating IL-6 and IL-8 production and E-selectin membrane expression.
        Am J Physiol Cell Physiol. 2003; 285: C1036-C1046
        • Silva G
        • Jeney V
        • Chora A
        • Larsen R
        • Balla J
        • Soares MP.
        Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells.
        J Biol Chem. 2009; 284: 29582-29595
        • Nyakundi BB
        • Toth A
        • Balogh E
        • et al.
        Oxidized hemoglobin forms contribute to NLRP3 inflammasome-driven IL-1beta production upon intravascular hemolysis.
        Biochim Biophys Acta Molecular Basis Dis. 2019; 1865: 464-475
        • Coronado LM
        • Nadovich CT
        • Spadafora C.
        Malarial hemozoin: from target to tool.
        Biochim Biophys Acta. 2014; 1840: 2032-2041
        • Shio MT
        • Eisenbarth SC
        • Savaria M
        • et al.
        Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases.
        PLoS Pathog. 2009; 5e1000559
        • Griffith JW
        • Sun T
        • McIntosh MT
        • Bucala R.
        Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid.
        J Immunol. 2009; 183: 5208-5220
        • Dostert C
        • Guarda G
        • Romero JF
        • et al.
        Malarial hemozoin is a Nalp3 inflammasome activating danger signal.
        PLoS One. 2009; 4: e6510
        • Coban C
        • Ishii KJ
        • Kawai T
        • et al.
        Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin.
        J Exp Med. 2005; 201: 19-25
        • Kawasaki T
        • Kawai T.
        Toll-like receptor signaling pathways.
        Front Immunol. 2014; 5: 461
        • Kalantari P
        • DeOliveira RB
        • Chan J
        • et al.
        Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria.
        Cell Rep. 2014; 6: 196-210
        • Coban C
        • Ishii KJ
        • Uematsu S
        • et al.
        Pathological role of Toll-like receptor signaling in cerebral malaria.
        Int Immunol. 2007; 19: 67-79
        • Parroche P
        • Lauw FN
        • Goutagny N
        • et al.
        Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9.
        Proc Natl Acad Sci U S A. 2007; 104: 1919-1924
        • Ryter SW
        • Alam J
        • Choi AM.
        Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications.
        Physiol Rev. 2006; 86: 583-650
        • Jung SS
        • Moon JS
        • Xu JF
        • et al.
        Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages.
        Am J Physiol Lung Cell Mol Physiol. 2015; 308: L1058-L1067
        • Lin Y
        • Wang S
        • Yang Z
        • et al.
        Bilirubin alleviates alum-induced peritonitis through inactivation of NLRP3 inflammasome.
        Biomed Pharmacother. 2019; 116108973
        • Luo YP
        • Jiang L
        • Kang K
        • et al.
        Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1.
        Int Immunopharmacol. 2014; 20: 24-32
        • Li H
        • Zhou X
        • Zhang J.
        Induction of heme oxygenase-1 attenuates lipopolysaccharide-induced inflammasome activation in human gingival epithelial cells.
        Int J Mol Med. 2014; 34: 1039-1044
        • Sundd P
        • Gladwin MT
        • Novelli EM.
        Pathophysiology of Sickle Cell Disease.
        Annu Rev Pathol. 2019; 14: 263-292
        • Kato GJ
        • Piel FB
        • Reid CD
        • et al.
        Sickle cell disease.
        Nat Rev Dis Primers. 2018; 4: 18010
        • Conran N
        • Belcher JD.
        Inflammation in sickle cell disease.
        Clin Hemorheol Microcirc. 2018; 68: 263-299
        • van Beers EJ
        • Yang Y
        • Raghavachari N
        • et al.
        Iron, inflammation, and early death in adults with sickle cell disease.
        Circ Res. 2015; 116: 298-306
        • Kaul DK
        • Hebbel RP.
        Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice.
        J Clin Invest. 2000; 106: 411-420
        • Belcher JD
        • Marker PH
        • Weber JP
        • Hebbel RP
        • Vercellotti GM.
        Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion.
        Blood. 2000; 96: 2451-2459
        • Beckman JD
        • Abdullah F
        • Chen C
        • et al.
        Endothelial TLR4 expression mediates vaso-occlusive crisis in sickle cell disease.
        Front Immunol. 2020; 11613278
        • Belcher JD
        • Chen C
        • Nguyen J
        • et al.
        Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease.
        Blood. 2014; 123: 377-390
        • Ghosh S
        • Adisa OA
        • Chappa P
        • et al.
        Extracellular hemin crisis triggers acute chest syndrome in sickle mice.
        J Clin Invest. 2013; 123: 4809-4820
        • Vercellotti GM
        • Zhang P
        • Nguyen J
        • et al.
        Hepatic overexpression of hemopexin inhibits inflammation and vascular stasis in murine models of sickle cell disease.
        Mol Med. 2016; 22: 437-451
        • Adisa OA
        • Hu Y
        • Ghosh S
        • Aryee D
        • Osunkwo I
        Ofori-Acquah SF. Association between plasma free haem and incidence of vaso-occlusive episodes and acute chest syndrome in children with sickle cell disease.
        Br J Haematol. 2013; 162: 702-705
        • Wagener FA
        • Feldman E
        • de Witte T
        • Abraham NG
        Heme induces the expression of adhesion molecules ICAM-1, VCAM-1, and E selectin in vascular endothelial cells.
        Proc Soc Exp Biol Med. 1997; 216: 456-463
        • Mako V
        • Czucz J
        • Weiszhar Z
        • et al.
        Proinflammatory activation pattern of human umbilical vein endothelial cells induced by IL-1beta, TNF-alpha, and LPS.
        Cytometry A. 2010; 77: 962-970
        • Hawrylowicz CM
        • Howells GL
        • Feldmann M.
        Platelet-derived interleukin 1 induces human endothelial adhesion molecule expression and cytokine production.
        J Exp Med. 1991; 174: 785-790
        • Miller LS
        • Pietras EM
        • Uricchio LH
        • et al.
        Inflammasome-mediated production of IL-1beta is required for neutrophil recruitment against Staphylococcus aureus in vivo.
        J Immunol. 2007; 179: 6933-6942
        • Prince LR
        • Allen L
        • Jones EC
        • et al.
        The role of interleukin-1beta in direct and toll-like receptor 4-mediated neutrophil activation and survival.
        Am J Pathol. 2004; 165: 1819-1826
        • Ghosh S
        • Adisa O
        • Yang Y
        • Tan F
        • Ofori-Acquah SF.
        Toll-like receptor 4 mediates heme induced acute lung injury: preclinical study of resatorvid in sickle cell disease.
        Blood. 2011; 118: 2113
        • Vogel S
        • Arora T
        • Wang X
        • et al.
        The platelet NLRP3 inflammasome is upregulated in sickle cell disease via HMGB1/TLR4 and Bruton tyrosine kinase.
        Blood Adv. 2018; 2: 2672-2680
        • Ito M
        • Shichita T
        • Okada M
        • et al.
        Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury.
        Nat Commun. 2015; 6: 7360
        • Liu X
        • Pichulik T
        • Wolz OO
        • et al.
        Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase.
        J Allergy Clin Immunol. 2017; 140 (e10): 1054-1067
        • Bennewitz MF
        • Jimenez MA
        • Vats R
        • et al.
        Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli.
        JCI Insight. 2017; 2: e89761
        • Vats R
        • Brzoska T
        • Bennewitz MF
        • et al.
        Platelet extracellular vesicles drive inflammasome-IL-1beta-dependent lung injury in sickle cell disease.
        Am J Respir Crit Care Med. 2020; 201: 33-46
        • Vinchi F
        • Costa da Silva M
        • Ingoglia G
        • et al.
        Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.
        Blood. 2016; 127: 473-486
        • Jentho E
        • Ruiz-Moreno C
        • Novakovic B
        • et al.
        Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme.
        Proc Natl Acad Sci U S A. 2021; 118e2102698118
        • Faro GB
        • Menezes-Neto OA
        • Batista GS
        • Silva-Neto AP
        • Cipolotti R.
        Left ventricular hypertrophy in children, adolescents and young adults with sickle cell anemia.
        Rev Bras Hematol Hemoter. 2015; 37: 324-328
        • Gbotosho OT
        • Kapetanaki MG
        • Ghosh S
        • Villanueva FS
        • Ofori-Acquah SF
        • Kato GJ.
        Heme induces IL-6 and cardiac hypertrophy genes transcripts in sickle cell mice.
        Front Immunol. 2020; 11: 1910
        • Cahill CM
        • Rogers JT.
        Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1.
        J Biol Chem. 2008; 283: 25900-25912
        • O'Brien LC
        • Mezzaroma E
        • Van Tassell BW
        • et al.
        Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure.
        Mol Med. 2014; 20: 221-229
        • Bujak M
        • Frangogiannis NG.
        The role of IL-1 in the pathogenesis of heart disease.
        Arch Immunol Ther Exp (Warsz). 2009; 57: 165-176
        • Prakash D
        • Fesel C
        • Jain R
        • Cazenave PA
        • Mishra GC
        Pied S. Clusters of cytokines determine malaria severity in Plasmodium falciparum-infected patients from endemic areas of Central India.
        J Infect Dis. 2006; 194: 198-207
        • Strangward P
        • Haley MJ
        • Albornoz MG
        • et al.
        Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria.
        Proc Natl Acad Sci U S A. 2018; 115: 7404-7409
        • Papayannopoulos V.
        Neutrophil extracellular traps in immunity and disease.
        Nat Rev Immunol. 2018; 18: 134-147
        • Folco EJ
        • Mawson TL
        • Vromman A
        • et al.
        Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1alpha and cathepsin G.
        Arterioscler Thromb Vasc Biol. 2018; 38: 1901-1912
        • Schimmel M
        • Nur E
        • Biemond BJ
        • et al.
        Nucleosomes and neutrophil activation in sickle cell disease painful crisis.
        Haematologica. 2013; 98: 1797-1803
        • Hounkpe BW
        • Chenou F
        • Domingos IF
        • et al.
        Neutrophil extracellular trap regulators in sickle cell disease: modulation of gene expression of PADI4, neutrophil elastase, and myeloperoxidase during vaso-occlusive crisis.
        Res Pract Thromb Haemost. 2021; 5: 204-210
        • Knackstedt SL
        • Georgiadou A
        • Apel F
        • et al.
        Neutrophil extracellular traps drive inflammatory pathogenesis in malaria.
        Sci Immunol. 2019; 4
        • Chen G
        • Zhang D
        • Fuchs TA
        • Manwani D
        • Wagner DD
        • Frenette PS.
        Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease.
        Blood. 2014; 123: 3818-3827
        • Kono M
        • Saigo K
        • Takagi Y
        • et al.
        Heme-related molecules induce rapid production of neutrophil extracellular traps.
        Transfusion (Paris). 2014; 54: 2811-2819
        • Munzer P
        • Negro R
        • Fukui S
        • et al.
        NLRP3 inflammasome assembly in neutrophils is supported by PAD4 and promotes NETosis under sterile conditions.
        Front Immunol. 2021; 12683803
        • Chen KW
        • Monteleone M
        • Boucher D
        • et al.
        Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps.
        Sci Immunol. 2018; 3: eaar6676
        • Sollberger G
        • Choidas A
        • Burn GL
        • et al.
        Gasdermin D plays a vital role in the generation of neutrophil extracellular traps.
        Sci Immunol. 2018; 3: eaar6689
        • Warnatsch A
        • Ioannou M
        • Wang Q
        Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis.
        Science. 2015; 349: 316-320
        • Gbotosho OT
        • Kapetanaki MG
        • Kato GJ.
        The worst things in life are free: the role of free heme in sickle cell disease.
        Front Immunol. 2020; 11561917
        • Mendonca R
        • Silveira AA
        • Conran N.
        Red cell DAMPs and inflammation.
        Inflamm Res. 2016; 65: 665-678
        • Lin S
        • Yin Q
        • Zhong Q
        • et al.
        Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage.
        J Neuroinflammation. 2012; 9: 46
        • Solovey A
        • Somani A
        • Belcher JD
        • et al.
        A monocyte-TNF-endothelial activation axis in sickle transgenic mice: therapeutic benefit from TNF blockade.
        Am J Hematol. 2017; 92: 1119-1130
        • Venugopal J
        • Wang J
        • Mawri J
        • Guo C
        • Eitzman D.
        Interleukin-1 receptor inhibition reduces stroke size in a murine model of sickle cell disease.
        Haematologica. 2020; 106: 2469-2477
        • Gentinetta T
        • Belcher JD
        • Brugger-Verdon V
        • et al.
        Plasma-derived hemopexin as a candidate therapeutic agent for acute vaso-occlusion in sickle cell disease: preclinical evidence.
        J Clin Med. 2022; : 11
        • Belcher JD
        • Chen C
        • Nguyen J
        • et al.
        Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: role of heme oxygenase-1 induction.
        PLoS One. 2018; 13e0196455
        • Belcher JD
        • Mahaseth H
        • Welch TE
        • Otterbein LE
        • Hebbel RP
        • Vercellotti GM.
        Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice.
        J Clin Invest. 2006; 116: 808-816
        • Vinchi F
        • De Franceschi L
        • Ghigo A
        • et al.
        Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases.
        Circulation. 2013; 127: 1317-1329
        • Rees DC
        • Kilinc Y
        • Unal S
        • et al.
        A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia.
        Blood. 2022; 139: 2642-2652
        • Osunkwo I
        • O'Connor HF
        • Saah E.
        Optimizing the management of chronic pain in sickle cell disease.
        Hematology Am Soc Hematol Educ Program. 2020; 2020: 562-569