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

Abstract

Background: Alcohol exposure induces TGFb1 and renders the lung susceptible to injury and disrepair. We determined that TGFb1 regulates myofibroblast differentiation through the loss of Thy-1 expression and consequent induction of a-SMA. TGFb1 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 TGFb1 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, TGFb1, and IL-17 and then analyzed for Thy-1 expression and cell morphology. Na€ ıve 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. TGFb1 or IL-17 exposure suppressed PLF Thy-1 expression. When administered together, TGFb1 and IL-17 additively down-regulated Thy-1 expression. Exposure of na€ ıve 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 a-SMA expression. Induction of a-SMA and myofibroblast morphology by IL-17 occurred selectively in a Thy-1 À 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 TGFb1 contribute to fibroproliferative disrepair in the lung and targeting these proteins could limit morbidity and mortality following lung injury in alcoholic individuals.

Chronic and Binge Alcohol Ingestion Increases Truncated Oxidized Phosphatidylcholines in Mice Lungs Due to Increased Oxidative Stress

“…Therefore, infiltrated neutrophils and/or lymphocytes might be responsible for increased IL-17 levels in BALF. Recent study demonstrated using 8 weeks alcohol drinking model in mice that alcohol-induced IL-17 and Th17 immune response promotes lung fibroblast differentiation to myofibroblasts ( Neveu et al, 2019 ), eventually this could cause fibroproliferative microenvironment in lungs of chronic alcohol drinkers. Therefore, IL-17 might be an important mediator in alcohol-induced lung injury and subsequent fibroproliferative disorders, which warrants further investigation.…”

Impacto do álcool no organismo: uma revisão dos mecanismos fisiopatológicos envolvidos na toxicidade sistêmica

“…Tal fato pode ser observado pelo aumento da concentração de marcadores de fibrose pulmonar como Timp 1, cadeias de colágeno tipo 1 (Col1a1), e α-SMA. (35,36) Outrossim, emerge uma clara evidência do papel crucial do sistema imunológico na perpetuação e agravamento do estado inflamatório, que eventualmente culmina na fibrose tecidual. A investigação dos marcadores da linhagem hematopoiética das células linfoides inatas do tipo 2 (ILC2) revela um incremento notável de KLRG1+ sob a influência do álcool, indicando uma intensificação da produção e ativação dessas células.…”

Thy-1-Integrin Interactions in cis and Trans Mediate Distinctive Signaling

“…Thy-1 is silenced within FF by epigenetic mechanisms, such as DNA methylation ( Sanders, Pardo et al, 2008 ). Epigenetic silencing of Thy-1 leading to pathogenic alteration in fibroblasts, is driven by aging and TGF-β ( Neveu, Mills et al, 2015 ), TLR4 ( Xing, Nie et al, 2015 ), IL-17 ( Neveu, Staitieh et al, 2019 ) and hypoxia ( Robinson, Neary et al, 2012 ). A recent study described a regulatory axis of Thy-1 expression involving the transcription factor YY1 and miR-214 in the context of lung fibrosis ( Chen, Yang et al, 2020 ).…”