title: IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis.
abstract: Obliterative bronchiolitis (OB), a fibrotic airway lesion, is the leading cause of death after lung transplantation. Type V collagen [col(V)] overexpression and IL-17-mediated anti-col(V) immunity are key contributors to OB pathogenesis. Here, we report a previously undefined role of IL-17 in inducing col(V) overexpression, leading to epithelial mesenchymal transition (EMT) and subsequent OB. We observed IL-17-mediated induction of col(V) α1 chains [α1 (V)] in normal airway epithelial cells in vitro and detected α1 (V)-specific antibodies in bronchoalveolar lavage fluid of lung transplant patients. Overexpression of IL-17 and col(V) was detected in OB lesions in patient lung biopsies and in a murine OB model. IL-17 is shown to induce EMT, TGF-β mRNA expression, and SMAD3 activation, whereas downregulating SMAD7 expression in vitro. Pharmacological inhibition of TGF-βRI tyrosine kinase, p38 MAPK, or focal adhesion kinase prevented col(V) overexpression and EMT. In murine orthotopic lung transplants, neutralizing IL-17 significantly decreased TGF-β mRNA and protein expression and prevented epithelial repair/OB. Our findings highlight a feed-forward loop between IL-17 and TGF-β, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation.
authors.affiliation: Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Ragini
authors.initials: R
authors.lastname: Vittal
authors.forename: Lin
authors.initials: L
authors.lastname: Fan
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Greenspan
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mickler
authors.forename: Bagavathi
authors.initials: B
authors.lastname: Gopalakrishnan
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gu
authors.forename: Heather L
authors.initials: HL
authors.lastname: Benson
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: William
authors.initials: W
authors.lastname: Burlingham
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Cummings
authors.forename: David S
authors.initials: DS
authors.lastname: Wilkes
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001991:Bronchitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002465:Cell Movement; D002478:Cells, Cultured; D024062:Collagen Type V / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008875:Middle Aged; D061251:Primary Cell Culture; D051381:Rats; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D001323:Autoantibodies; C530725:COL5A1 protein, human; D024062:Collagen Type V; D020381:Interleukin-17; D016212:Transforming Growth Factor beta