P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis
P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis
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DOI：
10.1038/s41467-019-10626-x
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发表时间：
2019-06-20
影响因子：
16.6
通讯作者：
Pelegrin, Pablo
中科院分区：
文献类型：
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作者：
Jose Martinez-Garcia, Juan;Martinez-Banaclocha, Helios;Pelegrin, Pablo
脓毒症的特征是全身炎症反应，随后是宿主的免疫抑制。代谢缺陷和线粒体衰竭在免疫功能低下的脓毒症患者中很常见。NLRP 3炎性体对于在被嘌呤能P2 X7受体激活后建立炎症反应是重要的。在这里，我们研究了一组患有腹腔内起源脓毒症的个体，并表明患者单核细胞通过P2 X7受体受损NLRP 3激活。此外，大多数脓毒症相关死亡发生在NLRP 3激活发生深刻改变的患者中。在脓毒症患者的单核细胞中，P2 X7受体与线粒体功能障碍相关。此外，P2 X7受体的激活导致线粒体损伤，这反过来又抑制HIF-1 α对NLRP 3的激活。我们表明，死亡率增加，在败血症的小鼠模型时，P2 X7受体在体内被激活。这些数据揭示了由P2 X7受体启动的分子机制，该机制有助于感染期间NLRP 3受损。
Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocom-promised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1 alpha. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.