[ODP6F] f. 免疫機構・ワクチン開発

[ODP-183] インフラマソームによるIL-1α成熟化におけるパイロトーシス実行因子ガスダーミンDの役割

○土屋 晃介，須田 貴司 (金沢大・がん・免疫炎症)

IL-1α serves as a pro-inflammatory cytokine. While pro-IL-1α has cytokine activity, proteolytic maturation may increase its potency and release from cells. IL-1α maturation occurs in a caspase-1-dependent manner following inflammasome activation. However, pro-IL-1α 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-1α maturation by non-particulate inflammasome activators. Ablation of GSDMD abrogated the maturation of IL-1α, but not of IL-1β. Inflammasome-induced maturation of IL-1α relied on extracellular Ca²⁺ and calpains. Ca²⁺ influx and calpain activation were induced in a GSDMD-dependent manner. Glycine, which inhibits cell lysis, but not GSDMD pore formation, did not affect IL-1α maturation. These results suggest that during inflammasome activation, GSDMD processed by caspase-1 forms plasma membrane pores that mediate Ca²⁺ influx, resulting in calpain-dependent maturation of IL-1α.