伤口愈合
医学
二硫仑
中性粒细胞胞外陷阱
糖尿病
糖尿病足溃疡
药理学
体内
糖尿病足
炎症
免疫学
内分泌学
生物
生物技术
作者
Shuofei Yang,Yu Feng,Liang Chen,Zheyu Wang,Jiaquan Chen,Qihong Ni,Xiangjiang Guo,Lan Zhang,Guanhua Xue
标识
DOI:10.1016/j.trsl.2022.10.008
摘要
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.
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