The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity

TLDR

Inflammasomes activate caspase‑1, which cleaves IL‑1β and IL‑18 into mature cytokines and drives pyroptosis, an inflammatory form of cell death. Genetic inactivation of caspase‑1 shows its protease activity is required for canonical IL‑1β secretion, pyroptosis, and immunity, and when GSDMD‑dependent pyroptosis is blocked, caspase‑8 is activated and a delayed, GSDMD‑independent lytic cell death releases large amounts of mature IL‑1, constituting a distinct pro‑inflammatory regulated necrosis.

Abstract

Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1C284A, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1C284A, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis.