Inhibiting NINJ1-dependent plasma membrane rupture protects against inflammasome-induced blood coagulation and inflammation.
Inhibiting NINJ1-dependent plasma membrane rupture protects against inflammasome-induced blood coagulation and inflammation.
复制标题
抑制 NINJ1 依赖性质膜破裂可防止炎症体诱导的凝血和炎症。
DOI：
10.1101/2023.08.30.555561
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Wu,Congqing
中科院分区：
文献类型：
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作者：
Cui,Jian;Li,Hua;Zhang,Guoying;Zhang,Yan;Yang,Ling;Sim,MarthaMS;Wood,JeremyP;Wei,Yinan;Li,Zhenyu;Wu,Congqing
在脓毒症和COVID等严重感染期间，全身血液凝固伴随着炎症。我们之前建立了凝血功能障碍和焦亡之间的联系，焦亡是对抗感染的重要防御机制。在焦亡过程中，质膜上形成气皮蛋白- d （GSDMD）孔，导致促凝剂组织因子（TF）阳性微泡（mv）的释放。缺乏GSDMD的小鼠释放的促凝剂mv较少。然而，将GSDMD激活与MV释放耦合的具体机制尚不清楚。最近有报道称，跨膜蛋白Ninjurin-1 （Ninjurin-1）积极介导了焦亡的质膜破裂（PMR）。在这里，我们发现NINJ1促进了焦亡过程中促凝剂MV的释放。单倍体功能不全或甘氨酸抑制NINJ1限制了促凝剂mv和炎性细胞因子的释放，部分保护了细菌鞭毛蛋白引发的凝血和致死性。我们的研究结果表明，nin1依赖性PMR在炎症小体诱导的血液凝固和炎症中起着至关重要的作用。
Systemic blood coagulation accompanies inflammation during severe infections like sepsis and COVID. We previously established a link between coagulopathy and pyroptosis, a vital defense mechanism against infection. 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 of these procoagulant MVs. However, the specific mechanisms coupling the 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. Haploinsufficiency 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.