RIPK3 collaborates with GSDMD to drive tissue injury in lethal polymicrobial sepsis
RIPK3 collaborates with GSDMD to drive tissue injury in lethal polymicrobial sepsis
复制标题
RIPK3 与 GSDMD 合作驱动致命性多微生物败血症的组织损伤
DOI：
10.1038/s41418-020-0524-1
复制
发表时间：
2020-03-09
影响因子：
12.4
通讯作者：
Xu, Yanfang
中科院分区：
文献类型：
--
作者：
Chen, Hui;Li, Yinshuang;Xu, Yanfang
脓毒症是一种全身性炎症疾病，可导致危及生命的多器官功能障碍。越来越多的证据表明，由病原体成分脂多糖（LPS）和炎性细胞因子引发的两种程序性坏死形式——坏死性凋亡和焦亡，在细菌性脓毒症诱导的休克和组织损伤的发展过程中发挥着重要作用。脓毒症诱导的休克和组织损伤需要受体相互作用蛋白激酶 - 3（RIPK3）和混合谱系激酶结构域样蛋白（MLKL）的磷酸化、半胱天冬酶11（caspase11）的激活以及gasdermin D（GSDMD）的裂解。然而，坏死性凋亡和焦亡在脓毒症病理进展中的协同作用仍不明确。在本研究中，我们发现同时阻断坏死性凋亡和焦亡（Ripk3 / Gsdmd或Mlkl / Gsdmd双敲除）可对小鼠脓毒性休克、全身凝血和多器官损伤起到累积性保护作用。骨髓移植实验证实，髓系和非髓系细胞中的坏死性凋亡和焦亡在脓毒症诱导的多器官损伤进展中不可或缺。RIPK3和GSDMD信号通路共同作用，放大巨噬细胞和内皮细胞中的坏死性炎症反应并促进组织因子释放，从而导致组织损伤。此外，Ripk3 / Gsdmd或Mlkl / Gsdmd双敲除可阻止炎性细胞因子和高迁移率族蛋白B1诱导的细胞死亡，这表明RIPK3 / MLKL与GSDMD机制及炎症之间存在正反馈回路，推动了脓毒症的进展。总之，我们的研究结果表明，在脓毒症过程中，RIPK3介导的坏死性凋亡和GSDMD介导的焦亡共同放大炎症信号并加剧组织损伤，这可能为这种高致死性疾病的联合治疗干预提供两个潜在靶点的新思路。
Sepsis is a systemic inflammatory disease causing life-threatening multi-organ dysfunction. Accumulating evidences suggest that two forms of programmed necrosis, necroptosis and pyroptosis triggered by the pathogen component lipopolysaccharide (LPS) and inflammatory cytokines, play important roles in the development of bacterial sepsis-induced shock and tissue injury. Sepsis-induced shock and tissue injury required receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) phosphorylation, caspase11 activation and gasdermin D (GSDMD) cleavage. However, the synergistic effect of necroptosis and pyroptosis in the pathological progress of sepsis remains elusive. In this study, we found that blockage of both necroptosis and pyroptosis (double deletion ofRipk3/GsdmdorMlkl/Gsdmd) resulted in accumulative protection against septic shock, systemic blood clotting and multi-organ injury in mice. Bone marrow transplantation confirmed that necroptosis and pyroptosis in both myeloid and nonmyeloid cells are indispensable in the progression of sepsis-induced multi-organ injury. Both RIPK3 and GSDMD signaling collaborated to amplify necroinflammation and tissue factor release in macrophages and endothelial cells, which led to tissue injury. Furthermore, cell death induced by inflammatory cytokines and high-mobility group box 1 could be prevented by double ablation ofRipk3/Gsdmd or Mlkl/Gsdmd, suggesting that a positive feedback loop interconnecting RIPK3/MLKL and GSDMD machinery and inflammation facilitated sepsis progression. Collectively, our findings demonstrated that RIPK3-mediated necroptosis and GSDMD-mediated pyroptosis collaborated to amply inflammatory signaling and enhance tissue injury in the process of sepsis, which may shed new light on two potential targets of combined therapeutic interventions for this highly lethal disorder.