IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Ragini Vittal, Lin Fan, Daniel S. Greenspan, Elizabeth A. Mickler, Bagavathi Gopalakrishnan, Hongmei Gu, Heather L. Benson, Chen Zhang, William Burlingham, Oscar W. Cummings, David S. Wilkes

Research output: Contribution to journalArticle

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)L401-L414
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume304
Issue number6
DOIs
StatePublished - 2013

Keywords

  • Autoimmunity
  • Epithelial-mesenchymal transition
  • Focal adhesion kinase
  • Mouse transplant model
  • p38 MAPK
  • RLE-6TN
  • Small-airway epithelial cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology
  • Medicine(all)

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    Vittal, R., Fan, L., Greenspan, D. S., Mickler, E. A., Gopalakrishnan, B., Gu, H., Benson, H. L., Zhang, C., Burlingham, W., Cummings, O. W., & Wilkes, D. S. (2013). IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis. American Journal of Physiology - Lung Cellular and Molecular Physiology, 304(6), L401-L414. https://doi.org/10.1152/ajplung.00080.2012