Alcohol-Induced Interleukin-17 Expression Causes Murine Lung Fibroblast-to-Myofibroblast Transdifferentiation via Thy-1 Down-Regulation

• Authors: Wendy Neveu, Emory University; Bashar Staitieh, Emory University; Stephen T. Mills, Emory University; David Guidot, Emory University; Viranuj Sueblinvong, Emory University
• Journal Title: Alcoholism: Clinical and Experimental Research
• Volume: Volume 43, Number 7
• Publisher: Wiley | 2019-07-01, Pages 1427-1438
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/acer.14110
• Subjects: Biology, Cell; Health Sciences, Immunology; Health Sciences, Health Care Management; Health Sciences, Nutrition
• Keywords: Science & Technology; Life Sciences & Biomedicine; Substance Abuse; Alcohol; Myofibroblast; Thy-1; Interleukin-17; Transforming Growth Factor beta 1; TGF-BETA; Fibrosis; Activation; Bleomycin; Cells; Infection; Severity; Injury; Abuse

Abstract

Background: Alcohol exposure induces TGFβ1 and renders the lung susceptible to injury and disrepair. We determined that TGFβ1 regulates myofibroblast differentiation through the loss of Thy-1 expression and consequent induction of α-SMA. TGFβ1 is important for T helper 17 (Th17) differentiation and IL-17 secretion, which in turn participates in tissue repair. We hypothesized that alcohol induces Th17 differentiation via TGFβ1 and that IL-17 produced by these cells contributes to the development of pro-fibrotic lung myofibroblasts. Methods: Primary lung fibroblasts (PLFs) were treated with alcohol, TGFβ1, and IL-17 and then analyzed for Thy-1 expression and cell morphology. Naïve and Th17-polarized CD4+ T cells were exposed to alcohol and assessed for IL-17 expression. CD4+ T cells from alcohol-fed mice were analyzed for Th17 and IL-17 expression. Lungs of control-fed, bleomycin-treated and alcohol-fed, bleomycin-treated mice were analyzed for IL-17 protein expression. Results: Alcohol-treated PLFs expressed lower levels of Thy-1 than untreated cells. TGFβ1 or IL-17 exposure suppressed PLF Thy-1 expression. When administered together, TGFβ1 and IL-17 additively downregulated Thy-1 expression. Exposure of naïve and Th17-polarized CD4+ T cells to alcohol induced the Th17 phenotype and augmented their production of IL-17. CD4+ Th17+ levels are elevated in the peripheral compartment but not in the lungs of alcohol-fed animals. Treatment of the PLFs with IL-17 and alcohol induced α-SMA expression. Induction of α-SMA and myofibroblast morphology by IL-17 occurred selectively in a Thy-1− fibroblast subpopulation. Chronic alcohol ingestion augmented lung-specific IL-17 expression following bleomycin-induced lung injury. Conclusion: Alcohol exposure skews T cells toward a Th17 immune response that in turn primes the lung for fibroproliferative disrepair through loss of Thy-1 expression and induction of myofibroblast differentiation. These effects suggest that IL-17 and TGFβ1 contribute to fibroproliferative disrepair in the lung and targeting these proteins could limit morbidity and mortality following lung injury in alcoholic individuals.