Assembly of inflammasomes after infection or injury leads to the release of interleukin-1b (IL-1b) and to pyroptosis. After inflammasome activation, cells either pyroptose or enter a hyperactivated state defined by IL-1b 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-1b production but reduced pyroptosis. Correspondingly, increasing SARM in cells caused less IL-1b release and more pyroptosis. SARM suppressed IL-1b by directly restraining the NLRP3 inflammasome and, hence, caspase-1 activation. Consistent with a role for SARM in pyroptosis, Sarm1 À/À mice were protected from lipopolysaccharide (LPS)-stimulated sepsis. Pyroptosisinducing, 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.

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