Gasdermin D mediates the maturation and release of IL-1α downstream of inflammasomes

IL-1 alpha serves as a pro-inflammatory cytokine. Although pro-IL-1 alpha has cytokine activity, proteolytic maturation increases its potency and release from cells. IL-1 alpha maturation occurs in a caspase-1-dependent manner following inflammasome activation. However, pro-IL-1 alpha is not a substrate of caspase-1, and it remains unclear what mediates the maturation of this cytokine downstream of inflammasomes. Here, we show that gasdermin D (GSDMD), an executor of pyroptosis, is required for the rapid induction of IL-1 alpha maturation by nonparticulate inflammasome activators. Ablation of GSDMD abrogates the maturation of IL-1 alpha, but not of IL-1 beta. Inflammasome-induced maturation of IL-1 alpha relies on extracellular Ca2+ and calpains. Ca2+ influx and calpain activation are induced in a GSDMD-dependent manner. Glycine, which inhibits cell lysis, but not GSDMD pore formation, does not affect IL-1 alpha maturation. These results suggest that during inflammasome activation, GSDMD processed by caspase-1 forms plasma membrane pores that mediate Ca2+ influx, resulting in the calpain-dependent maturation of IL-1 alpha.

Automated summary

This study demonstrates that GSDMD is essential for the rapid maturation of IL-1α by nonparticulate inflammasome activators. Ablation of GSDMD prevents the maturation of IL-1α but not IL-1β. The maturation of IL-1α induced by inflammasomes relies on extracellular calcium and calpains, which are induced in a GSDMD-dependent manner.