Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death
Hiroto Kambara,
Fei Liu,
Xiaoyu Zhang,
Peng Liu,
Besnik Bajrami,
Yan Teng,
Li Zhao,
Shiyi Zhou,
Hongbo Yu,
Weidong Zhou,
Leslie E. Silberstein,
Tao Cheng,
Mingzhe Han,
Yuanfu Xu,
Hongbo R. Luo
Affiliations
Hiroto Kambara
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
Fei Liu
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
Xiaoyu Zhang
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
Peng Liu
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
Besnik Bajrami
Center for Development of Therapeutics, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA
Yan Teng
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
Li Zhao
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
Shiyi Zhou
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
Hongbo Yu
VA Boston Healthcare System, Department of Pathology and Laboratory Medicine, Harvard Medical School, 1400 VFW Parkway, West Roxbury, MA 02132, USA
Weidong Zhou
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
Leslie E. Silberstein
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
Tao Cheng
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
Mingzhe Han
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
Yuanfu Xu
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
Hongbo R. Luo
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; Corresponding author
Summary: 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. : 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. Keywords: GSDMD, neutrophil death, neutrophil elastase, innate immunity, host defense
