Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM

Abstract

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.

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…Sterile α and HEAT Armadillo motif-containing protein (SARM) is a Toll-IL-1R domain-containing protein involved in cell death and innate immune responses. 53 SARM is required for the optimal induction of pyroptosis upon stimulation with nigericin, a classical NLRP3 activator. The precise mechanisms by which SARM enhances pyroptosis currently remain unclear; however, upon stimulation with nigericin, SARM clusters on mitochondria and mediates mitochondrial depolarization.…”

“…54 SARM clustering and mitochondrial depolarization were not induced by a stimulation with peptidoglycan. 53 Therefore, it currently remains unclear whether SARM clustering and mitochondrial depolarization contribute to pyroptosis, and the mechanisms by which SARM is activated upon inflammasome formation need to be elucidated.…”

“…44 However, because activators of canonical inflammasomes, but not the hyperactivating agent peptidoglycan, induce SARM clustering and mitochondrial depolarization, hyperactivation may also qualitatively differ from pyroptosis. 53 It has not yet been established whether hyperactivation functionally differs from pyroptosis. The release of IL-1β from living cells may exert stronger effects than that from pyroptotic cells on subsequent immunological events, such as the development of adaptive immune responses, if the former lasts longer than the latter.…”

Role reversal: adaptive immunity instructs inflammasome activation for anti‐viral defence

“…Labzin et al () found that NLRP3‐dependent lL‐1β secretion occurs in the absence of significant pyroptosis. This uncoupling of IL‐1β secretion and cell death is increasingly reported in the literature (Carty et al , ). How pyroptosis is limited in human macrophages is an intriguing conundrum, as it would be expected that active caspase‐1 will cleave both gasdermin‐D and pro‐IL‐1β.…”

“…is increasingly reported in the literature (Carty et al, 2019). How pyroptosis is limited in human macrophages is an intriguing conundrum, as it would be expected that active caspase-1 will cleave both gasdermin-D and pro-IL-1b.…”