Sensing of microbes activates the innate immune system, depending on functional mitochondria. However, pathogenic bacteria inhibit mitochondrial activity by delivering toxins via outer membrane vesicles (OMVs). How macrophages respond to pathogenic microbes that target mitochondria remains unclear. Here, we show that macrophages exposed to OMVs from Neisseria gonorrhoeae, uropathogenic Escherichia coli and Pseudomonas aeruginosa induce mitochondrial apoptosis and NLRP3 inflammasome activation. OMVs and toxins that cause mitochondrial dysfunction trigger inhibition of host protein synthesis, which depletes the unstable BCL-2 family member MCL-1 and induces BAK-dependent mitochondrial apoptosis. In parallel with caspase-11-mediated pyroptosis, mitochondrial apoptosis and potassium ion efflux activate the NLRP3 inflammasome after OMV exposure in vitro. Importantly, in the in vivo setting, the activation and release of interleukin-1β in response to N. gonorrhoeae OMVs is regulated by mitochondrial apoptosis. Our data highlight how innate immune cells sense infections by monitoring mitochondrial health.

取决于功能性线粒体，微生物的感觉会激活先天免疫系统。但是，病原细菌通过通过外膜囊泡（OMV）传递毒素来抑制线粒体活性。尚不清楚巨噬细胞如何针对靶向线粒体的病原微生物做出反应。在这里，我们显示巨噬细胞暴露于淋病奈瑟氏球菌，尿路致病性大肠杆菌和铜绿假单胞菌的OMV诱导线粒体凋亡和NLRP3炎性体活化。引起线粒体功能障碍的OMV和毒素触发宿主蛋白合成的抑制，从而耗尽了不稳定的BCL-2家族成员MCL-1，并诱导了BAK依赖性线粒体凋亡。与半胱天冬酶11介导的细胞凋亡同时发生，线粒体凋亡和钾离子外流在体外OMV暴露后激活NLRP3炎性体。重要的是，在体内环境中，响应于淋病奈瑟氏球菌OMV的白介素-1β的激活和释放受线粒体凋亡的调节。我们的数据强调了先天免疫细胞如何通过监测线粒体健康来感知感染。