IL-1? cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence-associated secretory phenotype.

ABSTRACT: Interleukin-1 alpha (IL-1?) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL-1? is produced after inflammasome activation and during cell senescence, but the protease cleaving IL-1? in these contexts is unknown. We show IL-1? is activated by caspase-5 or caspase-11 cleavage at a conserved site. Caspase-5 drives cleaved IL-1? release after human macrophage inflammasome activation, while IL-1? secretion from murine macrophages only requires caspase-11, with IL-1? release needing caspase-11 and caspase-1. Importantly, senescent human cells require caspase-5 for the IL-1?-dependent senescence-associated secretory phenotype (SASP) in vitro, while senescent mouse hepatocytes need caspase-11 for the SASP-driven immune surveillance of senescent cells in vivo. Together, we identify IL-1? as a novel substrate of noncanonical inflammatory caspases and finally provide a mechanism for how IL-1? is activated during senescence. Thus, targeting caspase-5 may reduce inflammation and limit the deleterious effects of accumulated senescent cells during disease and Aging.

SUBMITTER: Wiggins KA 

PROVIDER: S-EPMC6516163 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature