Requirement of Complement C6 for Intact Innate Immune Responses in Mice
Requirement of Complement C6 for Intact Innate Immune Responses in Mice
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DOI：
10.4049/jimmunol.1900801
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发表时间：
2020-07-01
影响因子：
4.4
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
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作者：
Fattahi, Fateme;Grailer, Jamison J.;Ward, Peter A.
在多微生物败血症的最初几天，存在先天免疫系统的强烈激活，导致促炎细胞因子和趋化因子的出现，沿着细胞外组蛋白的出现，其是高度促炎和促血栓形成的。在目前的研究中，我们研究了不同的先天性免疫反应的小鼠与敲除（KO）的补体蛋白6（C6）。来自这些KO小鼠的多形核中性粒细胞（PMN）具有缺陷的先天性免疫应答，包括表面粘附分子的缺陷表达、超氧阴离子的产生、PMN活化后活性氧簇的出现和组蛋白的释放，沿着缺陷的吞噬作用。此外，在C6（-/-）小鼠中，中性粒细胞和巨噬细胞中的NLRP 3炎性体都有缺陷。当这些KO小鼠遭受多微生物败血症时，它们的存活率得到改善，这与血浆中促炎细胞因子和趋化因子的水平降低以及血浆中组蛋白的水平降低有关。此外，在这些KO小鼠中，脓毒症诱导的心功能障碍减弱。在LPS诱导的急性肺损伤模型中，C6（-/-）小鼠表现出减少的PMN积聚和较少的肺上皮/内皮细胞功能障碍（水肿和出血）。这些数据表明，C6（-/-）小鼠具有降低的先天免疫应答，其导致更少的器官损伤和在多微生物脓毒症后改善的存活。
Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6(-/-) mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6(-/-) mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6(-/-) mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.