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抑制NINJ1依赖的质膜破裂可预防炎性小体诱导的血液凝固和炎症。

Inhibiting NINJ1-dependent plasma membrane rupture protects against inflammasome-induced blood coagulation and inflammation.

作者信息

Cui Jian, Li Hua, Ye Dien, Zhang Guoying, Zhang Yan, Yang Ling, Sim Martha M S, Wood Jeremy P, Wei Yinan, Li Zhenyu, Wu Congqing

机构信息

Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY.

Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, College Station, TX.

出版信息

bioRxiv. 2024 Dec 3:2023.08.30.555561. doi: 10.1101/2023.08.30.555561.

Abstract

Systemic blood coagulation accompanies inflammation during severe infection like sepsis and COVID. We've previously established a link between pyroptosis, a vital defense mechanism against infection, and coagulopathy. During pyroptosis, the formation of gasdermin-D (GSDMD) pores on the plasma membrane leads to the release of tissue factor (TF)-positive microvesicles (MVs) that are procoagulant. Mice lacking GSDMD release fewer TF MVs. However, the specific mechanisms leading from activation of GSDMD to MV release remain unclear. Plasma membrane rupture (PMR) in pyroptosis was recently reported to be actively mediated by the transmembrane protein Ninjurin-1 (NINJ1). Here we show that NINJ1 promotes procoagulant MV release during pyroptosis. Haploinsuffciency or glycine inhibition of NINJ1 limited the release of procoagulant MVs and inflammatory cytokines and partially protected against blood coagulation and lethality triggered by bacterial flagellin. Our findings suggest a crucial role for NINJ1-dependent PMR in inflammasome-induced blood coagulation and inflammation.

摘要

在脓毒症和新冠等严重感染期间,全身血液凝固与炎症相伴。我们之前已经在细胞焦亡(一种对抗感染的重要防御机制)和凝血病之间建立了联系。在细胞焦亡过程中,质膜上gasdermin-D(GSDMD)孔的形成导致促凝血的组织因子(TF)阳性微泡(MVs)释放。缺乏GSDMD的小鼠释放的TF MVs较少。然而,从GSDMD激活到MV释放的具体机制仍不清楚。最近有报道称,细胞焦亡中的质膜破裂(PMR)是由跨膜蛋白Ninjurin-1(NINJ1)主动介导的。在这里,我们表明NINJ1在细胞焦亡过程中促进促凝血MV的释放。NINJ1的单倍剂量不足或甘氨酸抑制限制了促凝血MV和炎性细胞因子的释放,并部分预防了由细菌鞭毛蛋白引发的血液凝固和致死性。我们的研究结果表明,NINJ1依赖性PMR在炎性小体诱导的血液凝固和炎症中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fee5/11639261/1e3473925038/nihpp-2023.08.30.555561v2-f0001.jpg

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