Caspase-1 initiates apoptosis in the absence of gasdermin D

TLDR

Caspase‑1 activation in inflammasomes triggers pyroptosis via gasdermin D, yet cells lacking GSDMD remain vulnerable to caspase‑1‑mediated death. We investigate the mechanism of caspase‑1‑initiated cell death in GSDMD‑deficient cells. Caspase‑1 induces apoptosis through a Bid‑caspase‑9‑caspase‑3 cascade, which may be followed by GSDME‑dependent secondary necrosis/pyroptosis. In GSDMD‑deficient macrophages, inflammasome activation triggers caspase‑1‑dependent apoptosis via caspase‑3, and chemical activation of caspase‑1 induces apoptosis rather than pyroptosis in these cells; Bid contributes but is not essential, and low‑GSDMD neurons and mast cells also undergo caspase‑1‑ and Bid‑dependent apoptosis, underscoring a distinct apoptotic pathway mediated by caspase‑1 in GSDMD‑low/null cells.

Abstract

Abstract Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells. Inflammasome stimuli induce apoptosis accompanied by caspase-3 activation in GSDMD-deficient macrophages, which largely relies on caspase-1. Chemical dimerization of caspase-1 induces pyroptosis in GSDMD-sufficient cells, but apoptosis in GSDMD-deficient cells. Caspase-1-induced apoptosis involves the Bid-caspase-9-caspase-3 axis, which can be followed by GSDME-dependent secondary necrosis/pyroptosis. However, Bid ablation does not completely abolish the cell death, suggesting the existence of an additional mechanism. Furthermore, cortical neurons and mast cells exhibit little or low GSDMD expression and undergo apoptosis after oxygen glucose deprivation and nigericin stimulation, respectively, in a caspase-1- and Bid-dependent manner. This study clarifies the molecular mechanism and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cell types.