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-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.

• Authors: Michael Carty, Jay Kearney, Katharine A Shanahan, Emily Hams, Ryoichi Sugisawa, Dympna Connolly, Ciara G Doran, Natalia Muñoz-Wolf, Claudia Gürtler, Katherine A Fitzgerald, Ed C Lavelle, Padraic G Fallon, Andrew G Bowie
• Journal: Immunity (Immunity) Vol. 50 Issue 6 Pg. 1412-1424.e6 (06 18 2019) ISSN: 1097-4180 [Electronic] United States
• PMID: 31076360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Armadillo Domain Proteins
• Biomarkers
• Cytokines
• Cytoskeletal Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• SARM1 protein, mouse

Topics

• Animals
• Armadillo Domain Proteins (genetics, metabolism)
• Biomarkers
• Cell Survival
• Cytokines (metabolism)
• Cytoskeletal Proteins (genetics, metabolism)
• Inflammasomes (metabolism)
• Macrophages (immunology, metabolism)
• Mice
• Mice, Knockout
• Mitochondria (genetics, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Protein Binding
• Pyroptosis
• Signal Transduction