Gasdermin D exerts anti-inflammatory effects by promoting neutrophil death

Gasdermin D (GSDMD) is considered a pro-inflammatory factor that mediates pyroptosis in macrophages to protect hosts from intracellular bacteria. Here we reveal that GSDMD deficiency paradoxically augmented host responses to extracellular Escherichia coli , mainly by delaying neutrophil death, establishing GSDMD as a negative regulator of innate immunity. In contrast to its activation in macrophages, in which activated inflammatory caspases cleave GSDMD to produce an N-terminal fragment (GSDMD-cNT) to trigger pyroptosis, GSDMD cleavage and activation in neutrophils was caspase independent. It was mediated by a neutrophil-specific serine protease, neutrophil elastase (ELANE), released from cytoplasmic granules into the cytosol in aging neutrophils. ELANE-mediated GSDMD cleavage was upstream of the caspase cleavage site and produced a fully active ELANE-derived N-terminal fragment (GSDMD-eNT) that induced lytic cell death as efficiently as GSDMD-cNT. Thus, GSDMD is pleiotropic, exerting both pro- and anti-inflammatory effects that make it a potential target for anti-bacterial and anti-inflammatory therapies.