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Alcohol‐Induced Interleukin‐17 Expression Causes Murine Lung Fibroblast‐to‐Myofibroblast Transdifferentiation via Thy‐1 Down‐Regulation
Author(s) -
Neveu Wendy A.,
Staitieh Bashar S.,
Mills Stephen T.,
Guidot David M.,
Sueblinvong Viranuj
Publication year - 2019
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14110
Subject(s) - myofibroblast , transdifferentiation , bleomycin , interleukin 17 , fibroblast , transforming growth factor , lung , chemistry , cellular differentiation , endocrinology , interleukin , biology , medicine , cell , cancer research , immunology , cytokine , fibrosis , in vitro , biochemistry , chemotherapy , gene
Background Alcohol exposure induces TGF β 1 and renders the lung susceptible to injury and disrepair. We determined that TGF β 1 regulates myofibroblast differentiation through the loss of Thy‐1 expression and consequent induction of α ‐ SMA . TGF β 1 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 TGF β 1 and that IL ‐17 produced by these cells contributes to the development of profibrotic lung myofibroblasts. Methods Primary lung fibroblasts ( PLF s) were treated with alcohol, TGF β 1, and IL ‐17 and then analyzed for Thy‐1 expression and cell morphology. Naïve and Th17‐polarized CD 4 + T cells were exposed to alcohol and assessed for IL ‐17 expression. CD 4 + 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 PLF s expressed lower levels of Thy‐1 than untreated cells. TGF β 1 or IL ‐17 exposure suppressed PLF Thy‐1 expression. When administered together, TGF β 1 and IL ‐17 additively down‐regulated Thy‐1 expression. Exposure of naïve and Th17‐polarized CD 4 + T cells to alcohol induced the Th17 phenotype and augmented their production of IL ‐17. CD 4 + Th17 + levels are elevated in the peripheral compartment but not in the lungs of alcohol‐fed animals. Treatment of the PLF s 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 TGF β 1 contribute to fibroproliferative disrepair in the lung and targeting these proteins could limit morbidity and mortality following lung injury in alcoholic individuals.