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

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 profibrotic 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 down‐regulated 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. Conclusions 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. Chronic alcohol ingestion has been associated with fibroproliferative disrepair following an acute lung injury. We show that chronic alcohol exposure induces the systemic Th17 immune response and the pro‐fibrotic cytokine IL‐17. These data present a nexus through which we can better understand the relationship between inflammation an