학술논문
Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation.
Document Type
Academic Journal
Author
Liu T; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Liu S; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; These authors contributed equally.; Rui X; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; These authors contributed equally.; Cao Y; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Hecker J; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Guo F; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Zhang Y; The Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Gong L; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Zhou Y; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Yu Y; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Krishnamoorthyni N; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Bates S; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Chun S; Division of Pulmonary Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.; Boyer N; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Xu S; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Park JA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Perrella MA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Levy BD; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Weiss ST; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Mou H; The Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Raby BA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Division of Pulmonary Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.; These authors jointly conceptualised and supervised this work.; Zhou X; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA xiaobo.zhou@channing.harvard.edu.; These authors jointly conceptualised and supervised this work.
Source
Publisher: European Respiratory Society Country of Publication: England NLM ID: 8803460 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1399-3003 (Electronic) Linking ISSN: 09031936 NLM ISO Abbreviation: Eur Respir J Subsets: MEDLINE
Subject
Language
English
Abstract
Rationale: Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes ( ISGs ). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning ISG induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown.
Objectives: To decipher the functions of gasdermin B (encoded by GSDMB ) in respiratory virus-induced lung inflammation.
Methods: In two independent cohorts, we analysed expression correlation between GSDMB and ISG s . In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB -overexpressing and GSDMB -deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo .
Results: GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection.
Conclusions: GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.
Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose.
(Copyright ©The authors 2024.)
Objectives: To decipher the functions of gasdermin B (encoded by GSDMB ) in respiratory virus-induced lung inflammation.
Methods: In two independent cohorts, we analysed expression correlation between GSDMB and ISG s . In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB -overexpressing and GSDMB -deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo .
Results: GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection.
Conclusions: GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.
Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose.
(Copyright ©The authors 2024.)