title: GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation.
abstract: Gasdermin B (GSDMB) on chromosome 17q21 demonstrates a strong genetic linkage to asthma, but its function in asthma is unknown. Here we identified that GSDMB is highly expressed in lung bronchial epithelium in human asthma. Overexpression of GSDMB in primary human bronchial epithelium increased expression of genes important to both airway remodeling [TGF-β1, 5-lipoxygenase (5-LO)] and airway-hyperresponsiveness (AHR) (5-LO). Interestingly, hGSDMBZp3-Cremice expressing increased levels of the human GSDMB transgene showed a significant spontaneous increase in AHR and a significant spontaneous increase in airway remodeling, with increased smooth muscle mass and increased fibrosis in the absence of airway inflammation. In addition, hGSDMBZp3-Cremice showed increases in the same remodeling and AHR mediators (TGF-β1, 5-LO) observed in vitro in GSDMB-overexpressing epithelial cells. GSDMB induces TGF-β1 expression via induction of 5-LO, because knockdown of 5-LO in epithelial cells overexpressing GSDMB inhibited TGF-β1 expression. These studies demonstrate that GSDMB, a gene highly linked to asthma but whose function in asthma is previously unknown, regulates AHR and airway remodeling without airway inflammation through a previously unrecognized pathway in which GSDMB induces 5-LO to induce TGF-β1 in bronchial epithelium.
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Sudipta
authors: S
authors: Das
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Marina
authors: M
authors: Miller
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Andrew K
authors: AK
authors: Beppu
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
authors: James
authors: J
authors: Mueller
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
authors: Matthew D
authors: MD
authors: McGeough
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Christine
authors: C
authors: Vuong
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Maya R
authors: MR
authors: Karta
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Peter
authors: P
authors: Rosenthal
authors: Meakins-Christie Laboratories of McGill University, McGill University, Montreal, QC, Canada H2X 2P2.|McGill University Health Center Research Institute, Montreal, QC, Canada H2X 2P2.
authors: Fazila
authors: F
authors: Chouiali
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Taylor A
authors: TA
authors: Doherty
authors: Department of Physiology and Biophysics, Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202.
authors: Richard C
authors: RC
authors: Kurten
authors: Meakins-Christie Laboratories of McGill University, McGill University, Montreal, QC, Canada H2X 2P2.|McGill University Health Center Research Institute, Montreal, QC, Canada H2X 2P2.
authors: Qutayba
authors: Q
authors: Hamid
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
authors: Hal M
authors: HM
authors: Hoffman
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093; dbroide@ucsd.edu.
authors: David H
authors: DH
authors: Broide
mesh_terms: D056151:Airway Remodeling / Q000235:genetics* / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D000094524:Gasdermins
chemical_list: D039741:Antigens, Dermatophagoides; D001094:Arachidonate 5-Lipoxygenase; D003094:Collagen; D016207:Cytokines; D020780:Matrix Metalloproteinase 9; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C527978:GSDMB protein, human; D000094524:Gasdermins
keywords: GSDMB; airway-hyperresponsiveness; asthma; inflammation; remodeling