title: Role of IL-17A in murine models of COPD airway disease.
abstract: Small airway fibrosis is a major pathological feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Chronic inflammatory cells accumulate around small airways in COPD and are thought to play a major role in small airway fibrosis. Mice deficient in α/β T cells have recently been shown to be protected from both experimental airway inflammation and fibrosis. In these models, CD4+Th17 cells and secretion of IL-17A are increased. However, a pathogenic role for IL-17 in specifically mediating fibrosis around airways has not been demonstrated. Here a role for IL-17A in airway fibrosis was demonstrated using mice deficient in the IL-17 receptor A (il17ra) Il17ra-deficient mice were protected from both airway inflammation and fibrosis in two different models of airway fibrosis that employ COPD-relevant stimuli. In these models, CD4+ Th17 are a major source of IL-17A with other expressing cell types including γδ T cells, type 3 innate lymphoid cells, polymorphonuclear cells, and CD8+ T cells. Antibody neutralization of IL-17RA or IL-17A confirmed that IL-17A was the relevant pathogenic IL-17 isoform and IL-17RA was the relevant receptor in airway inflammation and fibrosis. These results demonstrate that the IL-17A/IL-17 RA axis is crucial to murine airway fibrosis. These findings suggest that IL-17 might be targeted to prevent the progression of airway fibrosis in COPD.
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Minagawa
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takasaka
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Royce
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Moermans
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Saburo
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Internal Medicine, Respiratory Division, Jikei University, Tokyo, Japan; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Araya
authors.affiliation: Department of Inflammation Research, Amgen, Seattle, Washington.
authors.forename: Alison
authors.initials: A
authors.lastname: Budelsky
authors.affiliation: Department of Medicine, University of California, San Francisco, California.
authors.forename: Amanda
authors.initials: A
authors.lastname: Goodsell
authors.affiliation: Department of Medicine, University of California, San Francisco, California.
authors.forename: Jody L
authors.initials: JL
authors.lastname: Baron
authors.affiliation: Department of Pathology, University of California, San Francisco, California; stephen.nishimura@ucsf.edu.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D011014:Pneumonia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects
chemical_list: C491673:Il17ra protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D053722:Receptors, Interleukin-17; D011070:Poly I-C
keywords: airway; cigarette smoke; fibrosis; inflammation; interleukin-17