Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice.
Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice.
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DOI：
10.1172/jci.insight.147280
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发表时间：
2021-07-22
期刊：
影响因子：
8
通讯作者：
Adam AP
中科院分区：
文献类型：
--
作者：
Martino N;Ramos RB;Lu S;Leyden K;Tomaszek L;Sadhu S;Fredman G;Jaitovich A;Vincent PA;Adam AP
SOCS3是JAK/STAT3通路的主要抑制剂。该途径被白细胞介素6 （IL-6）激活，IL-6是休克期间细胞因子风暴的主要介质。为了确定其在血管休克反应中的作用，我们用非致死剂量的脂多糖（LPS）刺激缺乏SOCS3的成年内皮小鼠（SOCS3iEKO）。SOCS3iEKO小鼠在严重肾衰竭后16-24小时死亡。SOCS3的缺失导致lps诱导的I型ifn样程序和血栓形成前基因和前粘附基因的高表达。一致地，我们观察到腔内白细胞粘附和中性粒细胞胞外滞留（NETosis），以及视网膜静脉白质栓塞。值得注意的是，杂合子小鼠表现出一种中间表型，表明存在基因剂量效应。体外研究SOCS3蛋白水平在调节炎症反应中的作用。在人脐静脉内皮细胞中，脉冲追踪实验表明，SOCS3蛋白的半衰期小于20分钟。抑制SOCS3泛素化和蛋白酶体降解导致蛋白质积累和更强的抑制IL-6信号传导和屏障功能丧失。总之，我们的数据表明，SOCS3蛋白水平的调节对于抑制休克期间il -6介导的内皮病变至关重要，并提供了一种有希望的治疗途径，通过稳定内皮SOCS3来预防多器官功能障碍。
SOCS3 is the main inhibitor of the JAK/STAT3 pathway. This pathway is activated by interleukin 6 (IL-6), a major mediator of the cytokine storm during shock. To determine its role in the vascular response to shock, we challenged mice lacking SOCS3 in the adult endothelium (SOCS3iEKO) with a nonlethal dose of lipopolysaccharide (LPS). SOCS3iEKO mice died 16–24 hours postinjection after severe kidney failure. Loss of SOCS3 led to an LPS-induced type I IFN–like program and high expression of prothrombotic and proadhesive genes. Consistently, we observed intraluminal leukocyte adhesion and neutrophil extracellular trap–osis (NETosis), as well as retinal venular leukoembolization. Notably, heterozygous mice displayed an intermediate phenotype, suggesting a gene dose effect. In vitro studies were performed to study the role of SOCS3 protein levels in the regulation of the inflammatory response. In human umbilical vein endothelial cells, pulse-chase experiments showed that SOCS3 protein had a half-life less than 20 minutes. Inhibition of SOCS3 ubiquitination and proteasomal degradation led to protein accumulation and a stronger inhibition of IL-6 signaling and barrier function loss. Together, our data demonstrate that the regulation of SOCS3 protein levels is critical to inhibit IL-6–mediated endotheliopathy during shock and provide a promising therapeutic avenue to prevent multiorgan dysfunction through stabilization of endothelial SOCS3.
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影响因子：
3.9
作者：
Cunningham C
通讯作者：
Cunningham C
del妄作为重症疾病幸存者长期认知障碍的预测指标。
影响因子：
8.8
作者：
Girard TD;Jackson JC;Pandharipande PP;Pun BT;Thompson JL;Shintani AK;Gordon SM;Canonico AE;Dittus RS;Bernard GR;Ely EW
通讯作者：
Ely EW
影响因子：
7.1
作者：
Gussen, Hendrik;Hohlstein, Philipp;Tacke, Frank
通讯作者：
Tacke, Frank
影响因子：
1.7
作者：
Gurkan OU;He C;Zielinski R;Rabb H;King LS;Dodd-o JM;D'Alessio FR;Aggarwal N;Pearse D;Becker PM
通讯作者：
Becker PM
DOI：
10.1152/ajpheart.00292.2006
发表时间：
2006-09-01
影响因子：
4.8
作者：
Feletou, Michel;Vanhoutte, Paul M.
通讯作者：
Vanhoutte, Paul M.