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
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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.
