RRC ID 51235
Author Kambara H, Liu F, Zhang X, Liu P, Bajrami B, Teng Y, Zhao L, Zhou S, Yu H, Zhou W, Silberstein LE, Cheng T, Han M, Xu Y, Luo HR.
Title Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death.
Journal Cell Rep
Abstract Gasdermin D (GSDMD) is considered a proinflammatory 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, which established 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 NT 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 antibacterial and anti-inflammatory therapies.
Volume 22(11)
Pages 2924-2936
Published 2018-3-13
DOI 10.1016/j.celrep.2018.02.067
PII S2211-1247(18)30261-4
PMID 29539421
PMC PMC5878047
MeSH Animals Anti-Inflammatory Agents / pharmacology Anti-Inflammatory Agents / therapeutic use* Apoptosis Regulatory Proteins / pharmacology Apoptosis Regulatory Proteins / therapeutic use* Cell Death / drug effects* Humans Mice Neutrophils / drug effects*
IF 7.815
Times Cited 51
Resource
DNA material CSII-EF-RfA (RDB04385) CSII-CMV-MCS-IRES2-Bsd (RDB04385).