Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death

• Autor: Kambara, Hiroto ; Liu, Fei ; Zhang, Xiaoyu ; Liu, Peng ; Bajrami, Besnik ; Teng, Yan ; Zhao, Li ; Zhou, Shiyi ; Yu, Hongbo ; Zhou, Weidong ; Silberstein, Leslie E. ; Cheng, Tao ; Han, Mingzhe ; Xu, Yuanfu ; Luo, Hongbo R.
• Assuntos: Animals ; Anti-Inflammatory Agents - pharmacology ; Anti-Inflammatory Agents - therapeutic use ; Apoptosis Regulatory Proteins - pharmacology ; Apoptosis Regulatory Proteins - therapeutic use ; Cell Death - drug effects ; GSDMD ; host defense ; Humans ; innate immunity ; Intracellular Signaling Peptides and Proteins ; Mice ; neutrophil death ; neutrophil elastase ; Neutrophils - drug effects ; Phosphate-Binding Proteins
• É parte de: Cell reports (Cambridge), 2018-03, Vol.22 (11), p.2924-2936
• Notas: ObjectType-Article-1
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  These authors contributed equally
  
• Descrição: 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. [Display omitted] •GSDMD-deficient mice display augmented bactericidal activity against Escherichia coli•GSDMD is a key regulator of neutrophil death•Delayed neutrophil death leads to enhanced host defense in GSDMD-deficient mice•GSDMD cleavage in neutrophils is mediated by neutrophil elastase Kambara et al. find that GSDMD deficiency augments host responses to extracellular Escherichia coli, mainly by delaying neutrophil death, establishing GSDMD as a negative regulator of innate immunity. GSDMD cleavage and activation in neutrophils is mediated by ELANE, released from cytoplasmic granules into the cytosol in aging neutrophils.
  
• Editor: United States: Elsevier Inc
  
• Idioma: Inglês