Abstract
Diabetic foot ulcer (DFU) is among the most frequent complications of diabetes and
is associated with significant morbidity and mortality. Excessive neutrophil extracellular
traps (NETs) delay wound healing in diabetic patients. Therefore, interventions targeting
NET release need to be developed to effectively prevent NET-based wound healing impairment.
Gasdermin D (GSDMD), a pore-forming protein acts as a central executioner of inflammatory
cell death and can activate inflammasomes in neutrophils to release NETs. A precise
understanding of the mechanism underlying NET-mediated delay in diabetic wound healing
may be valuable in identifying potential therapeutic targets to improve clinical outcomes.
In this study, we reported that neutrophils were more susceptible to NETosis in diabetic
wound environments of patients with DFU. By in vitro experiments and using in vivo mouse models of diabetic wound healing (wide-type, Nlrp3−/−, Casp-1−/−, and Gsdmd−/− mice), we demonstrated that NLRP3/caspase-1/GSDMD pathway on activation controls
NET release by neutrophils in diabetic wound tissue. Furthermore, inhibition of GSDMD
with disulfiram or genic deletion of Gsdmd abrogated NET formation, thereby accelerating diabetic wound healing. Disulfiram
could inhibit NETs-mediated diabetic foot ulcer healing impairment by suppressing
the NLRP3/Caspase-1/GSDMD pathway. In summary, our findings uncover a novel therapeutic
role of disulfiram in inhibiting NET formation, which is of considerable value in
accelerating wound healing in patients with DFU.
Abbreviations:
Diabetic foot ulcer (DFU), Neutrophil extracellular traps (NETs), Gasdermin D (GSDMD), Peptidyl arginine deiminase 4 (PAD4), Cell-free double-stranded DNA (cfDNA), neutrophil elastase (NE), Wild-type (WT), Streptozotocin (STZ), 4',6-diamidino-2-phenylindole dihydrochloride (DAPI), Phosphate buffered saline (PBS), Lipopolysaccharides (LPS)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Wound healing and its impairment in the diabetic foot.Lancet (London, England). 2005; 366: 1736-1743
- Inflammatory cells during wound repair: the good, the bad and the ugly.Trends Cell Biol. 2005; 15: 599-607
- Neutrophil extracellular traps kill bacteria.Science. 2004; 303: 1532-1535
- PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures.Front Immunol. 2012; 3: 307
- Neutrophil extracellular traps (NETs) in autoimmune diseases: a comprehensive review.Autoimmun Rev. 2017; 16: 1160-1173
- Glucose induces metabolic reprogramming in neutrophils during type 2 diabetes to form constitutive extracellular traps and decreased responsiveness to lipopolysaccharides.Biochim Biophys Acta Mol Basis Dis. 2020; 1866165940
- The influence of hyperglycemia on neutrophil extracellular trap formation and endothelial glycocalyx damage in a mouse model of type 2 diabetes.Microcirculation. 2020; 27: e12617
- Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality.Cell Death Differ. 2011; 18: 581-588
- Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.Nat Med. 2015; 21: 815-819
- NETosis delays diabetic wound healing in mice and humans.Diabetes. 2016; 65: 1061-1071
- Neutrophil extracellular traps are markers of wound healing impairment in patients with diabetic foot ulcers treated in a multidisciplinary setting.Adv Wound Care. 2020; 9: 16-27
- Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion.Cell Res. 2015; 25: 1285-1298
- Function and regulation of noncanonical caspase-4/5/11 inflammasome.J Immunol. 2020; 204: 3063-3069
- A new research hot spot: the role of NLRP3 inflammasome activation, a key step in pyroptosis, in diabetes and diabetic complications.Life Sci. 2020; 240117138
- NLRP3 activation induced by neutrophil extracellular traps sustains inflammatory response in the diabetic wound.Clin Sci (Lond). 2019; 133: 565-582
- HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells.Cell Death Discov. 2022; 8: 112
- Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy.Acta Pharmacol Sin. 2021; 42: 954-963
- TLR4/NF-κB signaling induces GSDMD-related pyroptosis in tubular cells in diabetic kidney disease.Front Endocrinol (Lausanne). 2019; 10: 603
- NLRP3 Inflammasome assembly in neutrophils is supported by PAD4 and promotes NETosis under sterile conditions.Front Immunol. 2021; 12683803
- CLEC5A is critical in Pseudomonas aeruginosa-induced NET formation and acute lung injury.JCI Insight. 2022; 7: e156613
- Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.Pharmacol Rev. 2012; 64: 520-539
- FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation.Nat Immunol. 2020; 21: 736-745
- Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps.Sci Immunol. 2018; 3: eaar6676
- Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.Blood. 2021; 138: 2702-2713
- A new wound-based severity score for diabetic foot ulcers: a prospective analysis of 1,000 patients.Diabetes Care. 2006; 29: 988-992
- The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system correlates with cost of care for diabetic foot ulcers treated in a multidisciplinary setting.J Vasc Surg. 2018; 67: 1455-1462
- Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.Circ Res. 2009; 104: 1095-1102
- Soluble ST2 is regulated by p75 neurotrophin receptor and predicts mortality in diabetic patients with critical limb ischemia.Arterioscler Thromb Vasc Biol. 2012; 32: e149-e160
- Studying neutrophil migration in vivo using adoptive cell transfer.Methods Mol Biol. 2016; 1407: 179-194
- Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.Nature. 2015; 526: 660-665
- Gasdermin D plays a vital role in the generation of neutrophil extracellular traps.Sci Immunol. 2018; 3: eaar6689
- Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.Nat Chem Biol. 2015; 11: 189-191
- Neutrophil extracellular traps promote hypercoagulability in patients with sepsis.Shock (Augusta, Ga). 2017; 47: 132-139
- Cellular and molecular basis of wound healing in diabetes.J Clin Invest. 2007; 117: 1219-1222
- Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension.Arterioscler Thromb Vasc Biol. 2016; 36: 2078-2087
- The role of tumor-associated neutrophils in colorectal cancer.Int J Mol Sci. 2019; 20: 529
- The emerging roles of neutrophil extracellular traps in wound healing.Cell Death Dis. 2021; 12: 984
- Specific PKC betaII inhibitor: one stone two birds in the treatment of diabetic foot ulcers.Biosci Rep. 2018; 38BSR20171459
- Hydrogen sulfide primes diabetic wound to close through inhibition of NETosis.Mol Cell Endocrinol. 2019; 480: 74-82
- Modulating neutrophil extracellular traps for wound healing.Biomater Sci. 2020; 8: 3212-3223
- Neutrophil extracellular traps in immunity and disease.Nat Rev Immunol. 2018; 18: 134-147
- Disulfiram inhibits neutrophil extracellular trap formation and protects rodents from acute lung injury and SARS-CoV-2 infection.JCI Insight. 2022; 7: e157342
- Jack of all trades inhibits inflammation (in sober people).Nat Immunol. 2020; 21: 718-719
- Inflammasome-associated cell death: Pyroptosis, apoptosis, and physiological implications.Microbiol Immunol. 2020; 64: 252-269
- Gasdermin: a new player to the inflammasome game.Biomed J. 2017; 40: 313-316
- Inhibition of inflammasome activation improves the impaired pattern of healing in genetically diabetic mice.Br J Pharmacol. 2014; 171: 2300-2307
- Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice.Diabetes. 2014; 63: 1103-1114
- High Glucose Induces the Loss of Retinal Pericytes Partly via NLRP3-Caspase-1-GSDMD-Mediated Pyroptosis.Biomed Res Int. 2020; 20204510628
- Empagliflozin protects diabetic pancreatic tissue from damage by inhibiting the activation of the NLRP3/caspase-1/GSDMD pathway in pancreatic β cells: in vitro and in vivo studies.Bioengineered. 2021; 12: 9356-9366
- Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death.Cell Rep. 2018; 22: 2924-2936
- Degraded neutrophil extracellular traps promote the growth of Actinobacillus pleuropneumoniae.Cell Death Dis. 2019; 10: 657
Article info
Publication history
Published online: November 03, 2022
Accepted:
October 30,
2022
Received in revised form:
October 26,
2022
Received:
September 10,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Shuofei Yang and Yu Feng contribute equally to this article.
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
