School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Immunity. 2019 Jun 18;50(6):1412-1424.e6. doi: 10.1016/j.immuni.2019.04.005. Epub 2019 May 7.
Assembly of inflammasomes after infection or injury leads to the release of interleukin-1β (IL-1β) and to pyroptosis. After inflammasome activation, cells either pyroptose or enter a hyperactivated state defined by IL-1β secretion without cell death, but what controls these different outcomes is unknown. Here, we show that removal of the Toll-IL-1R protein SARM from macrophages uncouples inflammasome-dependent cytokine release and pyroptosis, whereby cells displayed increased IL-1β production but reduced pyroptosis. Correspondingly, increasing SARM in cells caused less IL-1β release and more pyroptosis. SARM suppressed IL-1β by directly restraining the NLRP3 inflammasome and, hence, caspase-1 activation. Consistent with a role for SARM in pyroptosis, Sarm1 mice were protected from lipopolysaccharide (LPS)-stimulated sepsis. Pyroptosis-inducing, but not hyperactivating, NLRP3 stimulants caused SARM-dependent mitochondrial depolarization. Thus, SARM-dependent mitochondrial depolarization distinguishes NLRP3 activators that cause pyroptosis from those that do not, and SARM modulation represents a cell-intrinsic mechanism to regulate cell fate after inflammasome activation.
在感染或损伤后，炎症小体的组装会导致白细胞介素-1β（IL-1β）的释放和细胞焦亡。炎症小体激活后，细胞要么发生细胞焦亡，要么进入细胞死亡但 IL-1β持续分泌的超激活状态，但控制这些不同结果的机制尚不清楚。在这里，我们发现从巨噬细胞中去除 Toll-IL-1R 蛋白 SARM 可使炎症小体依赖性细胞因子释放和细胞焦亡脱偶联，从而导致细胞中 IL-1β产生增加但细胞焦亡减少。相反，细胞中 SARM 的增加导致更少的 IL-1β释放和更多的细胞焦亡。SARM 通过直接抑制 NLRP3 炎症小体和半胱天冬酶-1 的激活来抑制 IL-1β。与 SARM 在细胞焦亡中的作用一致，Sarm1 小鼠对脂多糖（LPS）刺激的败血症有保护作用。引发细胞焦亡但不引发超激活的 NLRP3 激动剂会导致 SARM 依赖性线粒体去极化。因此，SARM 依赖性线粒体去极化区分了引起细胞焦亡的 NLRP3 激活剂和不引起细胞焦亡的激活剂，SARM 调节代表了炎症小体激活后调节细胞命运的细胞内固有机制。
