Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM
Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM
复制标题
DOI：
10.1016/j.immuni.2019.04.005
复制
发表时间：
2019-06-18
期刊：
影响因子：
32.4
通讯作者：
Bowie, Andrew G.
中科院分区：
文献类型：
--
作者：
Carty, Michael;Kearney, Jay;Bowie, Andrew G.
感染或损伤后炎性小体的组装导致白细胞介素-1 β（IL-1 β）的释放和焦亡。炎性小体激活后，细胞要么焦磷酸化，要么进入由IL-1 β分泌定义的超活化状态，而不发生细胞死亡，但控制这些不同结果的因素尚不清楚。在这里，我们表明，从巨噬细胞中去除Toll-IL-1 R蛋白SARM解除了炎性小体依赖性细胞因子释放和细胞凋亡，从而细胞显示IL-1 β产生增加，但减少了细胞凋亡。相应地，增加细胞中的SARM导致更少的IL-1 β释放和更多的焦亡。SARM通过直接抑制NLRP 3炎性体并因此抑制半胱天冬酶-1活化来抑制IL-1 β。与SARM在焦亡中的作用一致，SARM 1（-/-）小鼠受到脂多糖（LPS）刺激的脓毒症的保护。Pyroposis-inducing，但不过度活化，NLRP 3兴奋剂引起SARM依赖性线粒体去极化。因此，SARM依赖性线粒体去极化区分引起焦亡的NLRP 3激活剂与不引起焦亡的NLRP 3激活剂，并且SARM调节代表了在炎性小体激活后调节细胞命运的细胞内在机制。
Assembly of inflammasomes after infection or injury leads to the release of interleukin-1 beta (IL-1 beta) and to pyroptosis. After inflammasome activation, cells either pyroptose or enter a hyperactivated state defined by IL-1 beta 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-1 beta production but reduced pyroptosis. Correspondingly, increasing SARM in cells caused less IL-1 beta release and more pyroptosis. SARM suppressed IL-1 beta 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.