Summary: IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1β secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1β secretion by pyroptotic and non-pyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1β from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1β release in vitro and in vivo proceeds independently of GSDMD. IL-1β maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1β from resting, non-pyroptotic macrophages, but the speed of IL-1β release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1β cleavage induces IL-1β enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1β secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1β trafficking facilitates its unconventional secretion. : Interleukin-1β is a potent pro-inflammatory cytokine whose dysregulated production drives a myriad of human diseases. Monteleone et al. uncover the trafficking mechanisms driving the unconventional secretion of mature interleukin-1β in non-pyroptotic and pyroptotic myeloid cells and reveal functions for caspase-1 and GSDMD therein. Keywords: interleukin-1, unconventional protein secretion, inflammasome, caspase-1, macrophage, neutrophil, gasdermin, pyroptosis, trafficking, phosphoinositides
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