Abstract:
: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.
journal_name
Immunityjournal_title
Immunityauthors
Carty M,Kearney J,Shanahan KA,Hams E,Sugisawa R,Connolly D,Doran CG,Muñoz-Wolf N,Gürtler C,Fitzgerald KA,Lavelle EC,Fallon PG,Bowie AGdoi
10.1016/j.immuni.2019.04.005subject
Has Abstractpub_date
2019-06-18 00:00:00pages
1412-1424.e6issue
6eissn
1074-7613issn
1097-4180pii
S1074-7613(19)30185-2journal_volume
50pub_type
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