Interleukin-1 Beta Maturation Triggers Its Relocation To The Plasma Membrane For Gasdermin-D-Dependent And -Independent Secretion

IL-1 beta requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1 beta secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1 beta secretion by pyroptotic and nonpyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1 beta from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1 beta release in vitro and in vivo proceeds independently of GSDMD. IL-1 beta maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1 beta from resting, non-pyroptotic macrophages, but the speed of IL-1 beta release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1 beta cleavage induces IL-1 beta enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1 beta secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1 beta trafficking facilitates its unconventional secretion.