title: Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms.
abstract: Pulmonary fibrosis is the pathologic basis for a variety of incurable human chronic lung diseases. IL-17A, a glycoprotein secreted from IL-17-producing cells, has recently been shown to be a proinflammatory cytokine involved in chronic inflammation and autoimmune disease. In this study, we report that IL-17A increased the synthesis and secretion of collagen and promoted the epithelial-mesenchymal transition in alveolar epithelial cells in a TGF-β1-dependent manner. Using in vivo fibrotic models, we found IL-17A expression to be elevated and IL-17A-associated signaling pathways to be activated in fibrotic lung tissues. Neutralization of IL-17A in vivo promoted the resolution of bleomycin-induced acute inflammation, attenuated pulmonary fibrosis, and increased survival. Additionally, IL-17A antagonism inhibited silica-induced chronic inflammation and pulmonary fibrosis. Targeting IL-17A resulted in a shift of the suppressive immune response in fibrotic lung tissue toward a Th1-type immune response, and it effectively induced autophagy, which promoted the autophagic degradation of collagen and autophagy-associated cell death. Moreover, IL-17A was found to attenuate the starvation-induced autophagy, and autophagy modulators regulated collagen degradation in the alveolar epithelial cells in a TGF-β1-independent manner. Administration of 3-methylamphetamine, an autophagy inhibitor, reversed the therapeutic efficacy of IL-17A antagonism in pulmonary fibrosis. Our studies indicate that IL-17A participates in the development and progression of pulmonary fibrosis in both TGF-β1-dependent and -independent manners and that the components of the IL-17A signaling pathway are potential therapeutic targets for the treatment of fibroproliferative lung diseases.
authors.affiliation: Molecular Immunology and Pharmacology Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors.forename: Su
authors.initials: S
authors.lastname: Mi
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Jia-Ping
authors.initials: JP
authors.lastname: Wang
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Ma
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Wang
authors.forename: Han-Zhi
authors.initials: HZ
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002469:Cell Separation; D003094:Collagen / Q000096:biosynthesis; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D053773:Transforming Growth Factor beta1; D003094:Collagen