Abstract

Abstract The pro‐inflammatory cytokine IL‐1β is well known for its role in host defense and the initiation of potent inflammatory responses. It is processed from its inactive pro‐form by the inflammatory caspase‐1 into its mature bioactive form, which is then released from the cell via an unconventional secretion mechanism. Recently, gasdermin‐D has been identified as a new target of caspase‐1. After proteolytical cleavage of gasdermin‐D, the N‐terminal fragment induces pyroptosis, a lytic cell death, by forming large permeability pores in the plasma membrane. Here we show using the murine system that gasdermin‐D is required for IL‐1β secretion by macrophages, dendritic cells and partially in neutrophils, and that secretion is a cell‐lysis‐independent event. Liposome transport assays in vitro further demonstrate that gasdermin‐D pores are large enough to allow the direct release of IL‐1β. Moreover, IL‐18 and other small soluble cytosolic proteins can also be released in a lysis‐independent but gasdermin‐D‐dependent mode, suggesting that the gasdermin‐D pores allow passive the release of cytosolic proteins in a size‐dependent manner.