Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent.
Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4(+) and gammadelta(+) T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a(-/-) mice confirmed an essential role for IL-17A. Mechanistically, using ifngamma(-/-), il10(-/-), il10(-/-)il12p40(-/-), and il10(-/-)il17a(-/-) mice and TGF-beta blockade, we demonstrate that IL-17A-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced IL-17A production was also TGF-beta dependent, and recombinant IL-17A-mediated fibrosis required TGF-beta, suggesting cooperative roles for IL-17A and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by IL-1beta, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1beta were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.
Wilson
Mark S
MS
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Madala
Satish K
SK
Ramalingam
Thirumalai R
TR
Gochuico
Bernadette R
BR
Rosas
Ivan O
IO
Cheever
Allen W
AW
Wynn
Thomas A
TA
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D020381:Interleukin-17 / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D053583:Interleukin-1beta / Q000009:adverse effects* / Q000096:biosynthesis; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000276:immunology; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000150:complications
D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D020381:Interleukin-17; D053583:Interleukin-1beta; D001761:Bleomycin; D016753:Interleukin-10; D007371:Interferon-gamma