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Cell Rep. 2018 Mar 13;22(11):2924-2936. doi: 10.1016/j.celrep.2018.02.067.

Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death.

Author information

1
Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA 02215, USA; Department of Laboratory Medicine, Children's Hospital Boston, Enders Research Building, Room 814, Boston, MA 02115, USA.
2
The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
3
Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA 02215, USA; Department of Laboratory Medicine, Children's Hospital Boston, Enders Research Building, Room 814, Boston, MA 02115, USA; The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
4
Center for Development of Therapeutics, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
5
VA Boston Healthcare System, Department of Pathology and Laboratory Medicine, Harvard Medical School, 1400 VFW Parkway, West Roxbury, MA 02132, USA.
6
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
7
Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA 02215, USA; Department of Laboratory Medicine, Children's Hospital Boston, Enders Research Building, Room 814, Boston, MA 02115, USA. Electronic address: hongbo.luo@childrens.harvard.edu.

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.

KEYWORDS:

GSDMD; host defense; innate immunity; neutrophil death; neutrophil elastase

PMID:
29539421
PMCID:
PMC5878047
DOI:
10.1016/j.celrep.2018.02.067
[Indexed for MEDLINE]
Free PMC Article

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