| First Author | Carty M | Year | 2019 |
| Journal | Immunity | Volume | 50 |
| Issue | 6 | Pages | 1412-1424.e6 |
| PubMed ID | 31076360 | Mgi Jnum | J:282401 |
| Mgi Id | MGI:6380813 | Doi | 10.1016/j.immuni.2019.04.005 |
| Citation | Carty M, et al. (2019) Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM. Immunity 50(6):1412-1424.e6 |
| abstractText | Assembly of inflammasomes after infection or injury leads to the release of interleukin-1beta (IL-1beta) and to pyroptosis. After inflammasome activation, cells either pyroptose or enter a hyperactivated state defined by IL-1beta 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-1beta production but reduced pyroptosis. Correspondingly, increasing SARM in cells caused less IL-1beta release and more pyroptosis. SARM suppressed IL-1beta 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. |
