The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Cell Rep. 2018 Nov 27;25(9):2339-2353.e4. doi: 10.1016/j.celrep.2018.10.103.
Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1β. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1β maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1β maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1β release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro-inflammatory signals and provide an explanation as to why IL-1β activation is often associated with cellular stress, such as during chemotherapy.
BAX/BAK 介导的线粒体膜损伤导致的内在凋亡被认为是免疫沉默的。我们在这里表明，在巨噬细胞中，BAX/BAK 的激活导致凋亡抑制蛋白 (IAP) 降解，从而促进 caspase-8 介导的 IL-1β 激活。此外，BAX/BAK 信号诱导一条平行途径，通过 NLRP3 炎性小体介导的 caspase-1 依赖性 IL-1β 成熟，需要钾外流。值得注意的是，在 BAX/BAK 激活后，凋亡执行器 caspase-3 和 caspase-7 在上游作用于 caspase-8 和 NLRP3 诱导的 IL-1β 成熟和分泌。相反，细胞焦亡效应物 GSDMD 和 GSDME 对于 BAX/BAK 诱导的 IL-1β 释放不是必需的。这些发现强调了经历 BAX/BAK 介导的细胞凋亡的固有免疫细胞有能力产生促炎信号，并解释了为什么 IL-1β 的激活通常与细胞应激相关，如在化疗期间。
