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

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