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

Abstract

erative 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) ␣1 chains [␣1 (V)] in normal airway epithelial cells in vitro and detected ␣1 (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-␤ mRNA expression, and SMAD3 activation, whereas downregulating SMAD7 expression in vitro. Pharmacological inhibition of TGF-␤RI 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-␤ mRNA and protein expression and prevented epithelial repair/ OB. Our findings highlight a feed-forward loop between IL-17 and TGF-␤, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation. autoimmunity; p38 MAPK; focal adhesion kinase; small-airway epithelial cells; RLE-6TN; mouse transplant model; epithelial-mesenchymal transition OBLITERATIVE BRONCHIOLITIS (OB) is characterized by extensive peribronchiolar fibrosis with plugs of granulation tissues (fibroblasts and collagen) that occlude small airways. OB is the key reason that the 5-yr survival of lung transplant recipients is only 50%, the worst of all major solid organ transplants (42,48).Aberrant epithelial repair is a key event in the transplanted lung (1, 9) in which bronchioles lose resident epithelial cells and become occluded by granulation tissue. Abnormal epithelial repair eventually causes an epithelial-to-mesenchymal transition (EMT), a functional and phenotypic change of epithelial cells into spindle-shaped, migratory (43) and matrix-component-secreting mesenchymal cells (10, 41), and a process associated with lung fibrosis (15,27). However, the direct connection between EMT and the in vivo phenomena of fibrosis and fibro-obliterative disease remains controversial.We and others previously reported that OB is associated with dysregulation of two types of collagen: 1) marked increase in type V collagen [col(V)], a quantitatively minor lung collagen (8,14,40), and 2) a decrease in the major lung collagen type I [col(I)] (2, 53). We have shown that prospective monitoring of patients with human lung transplant revealed a critical role of col(V)-specific cellular immunity in OB pathogenesis (14,40). Although overexpression of col(V), an otherwise quantitatively minor collagen, is involved in OB pathology, mechanisms leading to col(V) overexpression are unknown. Thus a mechanistic understanding of the triggers of col(V)...

Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

“…4). These results indicate that IL-17A induces HIBECs-EMT in vitro, consistent with the results that IL-17A can also induce EMT in alveolar and bronchial epithelial cells (Mi et al 2011;Ji et al 2013;Vittal et al 2013). These results indicated that IL-17A played a potential role in inducing EMT of IBECs and subsequent peribiliary fibrosis.…”

“…Additionally, IL-17A induced EMT of epithelial cells (Mi et al 2011;Ji et al 2013;Vittal et al 2013). Therefore, to explore the association between IL-17A and IBECs-EMT, we first compared serum IL-17A concentrations between healthy controls and PBC patients.…”

“…Interleukin-17 (IL-17A), a typical pro-inflammatory cytokine, has recently been shown to induce EMT of alveolar epithelial cells (Mi et al 2011) and bronchial epithelial cells (Ji et al 2013;Vittal et al 2013). Interestingly, fre-quencies of IL-17A -positive lymphocytic cells are increased in the liver of PBC patients (Lan et al 2009) and IL-17A expression is elevated in peripheral blood of PBC patients (Qian et al 2013).…”

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

“…Advances in understanding the effects of allograft cellular senescence (accelerated ageing) on allograft function and BOS risk are needed, and a better understanding of the role of interleukin-17 [150][151][152][153][154][155][156], autoimmune pathways, regulatory lymphocyte populations [157][158][159][160][161][162][163] and neutrophil responses, as well as mechanisms by which the hypothetical phenomenon of epithelial-mesenchymal transition (which remains hypothetical and has not been well validated in humans) [164][165][166][167] leads to airway fibrosis, may lead to novel therapies to prevent and treat BOS. Improved animal models of OB are needed and are likely to be useful in improving our understanding of the role of these and other phenomena in the initiation, progression, prevention and treatment of OB following lung transplantation.…”

International practical guidelines on diagnosis, prevention and treatment of bronchiolitis obliterans syndrome

“…Следует развивать современные знания о влия нии клеточного старения трансплантата (ускоренно го старения) на его функцию и риск развития СОБ, а также о роли интерлейкина 17 [150][151][152][153][154][155][156], аутоим мунных механизмов, популяций регуляторных лим фоцитов [157][158][159][160][161][162][163], нейтрофильного ответа и меха низмов, приводящих к фиброзу дыхательных путей при гипотетическом феномене эпителиально мезен химальной трансформации (который пока остается гипотетическим и недостаточно хорошо доказан на моделях животных) [164][165][166][167]. При помощи этой информации возможно разработать новые методы терапии, направленные на предотвращение и лече ние СОБ.…”