title: Airway epithelial cells initiate the allergen response through transglutaminase 2 by inducing IL-33 expression and a subsequent Th2 response.
abstract: BACKGROUND
  Transglutaminase 2 (TG2) is a post-translational protein-modifying enzyme that catalyzes the transamidation reaction, producing crosslinked or polyaminated proteins. Increased TG2 expression and activity have been reported in various inflammatory conditions, such as rheumatoid arthritis, inflammation-associated pulmonary fibrosis, and autoimmune encephalitis. In particular, TG2 from epithelial cells is important during the initial inflammatory response in the lung. In this study, we evaluated the role of TG2 in the pathogenesis of allergic asthma, particularly whether TG2 affects initial activation signaling leading to Th2 differentiation against antigens.
  
  
  METHODS
  We induced allergic asthma by ovalbumin sensitization and intranasal challenge in wild-type (WT) BALB/c and TG2-deficient mice. Broncheoalveolar lavage fluid cells and intracellular cytokine production were analyzed by flow cytometry. Interleukin (IL)-33 and TG2 expression in lung epithelial cells was detected by confocal microscopy.
  
  
  RESULTS
  Airway responsiveness was attenuated in TG2-deficient mice compared to that in the WT control. In addition, recruitment of eosinophils and Th2 and Th17 differentiation decreased in TG2-deficient mice. Treatment with cysteamine, a transglutaminase inhibitor, also reduced airway hypersensitivity, inflammatory cell recruitment, and T helper cell differentiation. TG2-deficient mice showed reduced IL-33 expression following induction of allergic asthma compared to those in the WT control.
  
  
  CONCLUSIONS
  We found that pulmonary epithelial cells damaged by allergens triggered TG2-mediated IL-33 expression leading to type 2 responses by recruiting both innate and adaptive arms of the immune system.
authors.affiliation: Department of Biomedical Sciences, Laboratory of Immunology and Cancer Biology, Seoul, Korea.
authors.forename: Keunhee
authors.initials: K
authors.lastname: Oh
authors.forename: Myung Won
authors.initials: MW
authors.lastname: Seo
authors.forename: Ga Young
authors.initials: GY
authors.lastname: Lee
authors.forename: Ok-Jin
authors.initials: OJ
authors.lastname: Byoun
authors.forename: Hye-Ryun
authors.initials: HR
authors.lastname: Kang
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Cho
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D011503:Transglutaminases / Q000276:immunology / Q000378:metabolism*
chemical_list: D000485:Allergens; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins