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Mechanisms by which chronic ethanol feeding impairs the migratory capacity of cutaneous dendritic cells.

ABSTRACT: Chronic alcoholism is associated with increased incidence and severity of skin infection. Cutaneous dendritic cells (CDCs) play a pivotal role in skin immunity, and chronic ethanol (EtOH) feeding in mice has been shown to inhibit CDC migration to skin-draining lymph nodes (dLNs) following epicutaneous sensitization. Because CDC subsets differentially initiate T-cell responses, it is important to determine how EtOH feeding affects migration of each subset and identify mechanisms responsible for observed defects.Mice received EtOH in the drinking water for ? 16 weeks. Baseline numbers of CDC subsets and their migration to the dLNs following fluorescein 5-isothiocyanate (FITC) sensitization were assessed by flow cytometry. Epidermal cell suspension and skin explant cultures were used to measure the impact of EtOH upon molecules that influence CDC migration. Cytokine arrays performed on explant culture supernatants assessed local production of inflammatory cytokines.Chronic EtOH feeding reduced migration of all CDC subsets to the dLNs following FITC sensitization. Reduced migration of dermal-resident CDCs did not correspond with reduced baseline numbers of these cells. For Langerhans cells (LCs), EtOH-induced migratory dysfunction corresponded with delayed down-regulation of E-cadherin, chemokine receptor 1 (CCR1), and CCR6 and impaired up-regulation of matrix metalloproteinases (MMPs) 2 and 9. In skin explant assays, EtOH blunted CDC mobilization following stimulation with CCL21/CPG 1826. No alteration in CD54 or CCR7 expression was observed, but production of skin-derived tumor necrosis factor alpha (TNF-?) was reduced. Poor migratory responses in vitro could be improved by supplementing explant cultures from EtOH-fed mice with TNF-?.Chronic EtOH consumption does not alter baseline dermal-resident CDC numbers. However, like LCs, migratory responsiveness of dermal CDCs was decreased following FITC sensitization. Inefficient down-regulation of both CCRs and adhesion molecules and the inability to up-regulate MMPs indicate that EtOH impedes LC acquisition of a promigratory phenotype. These defects, combined with improvement of the migratory defect with in vitro TNF-? replacement, demonstrate intrinsic as well as environmental contributions to defective CDC migration. These findings provide novel mechanisms to explain the observed increased incidence and severity of skin infections in chronic alcoholics.

SUBMITTER: Parlet CP

PROVIDER: S-EPMC3815521 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Mechanisms by which chronic ethanol feeding impairs the migratory capacity of cutaneous dendritic cells.

Parlet Corey P CP Schlueter Annette J AJ

Alcoholism, clinical and experimental research 20130729 12

<h4>Background</h4>Chronic alcoholism is associated with increased incidence and severity of skin infection. Cutaneous dendritic cells (CDCs) play a pivotal role in skin immunity, and chronic ethanol (EtOH) feeding in mice has been shown to inhibit CDC migration to skin-draining lymph nodes (dLNs) following epicutaneous sensitization. Because CDC subsets differentially initiate T-cell responses, it is important to determine how EtOH feeding affects migration of each subset and identify mechanism ...[more]

PMID: 23895590

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Project description:Chronic alcoholism is associated with increased incidence and severity of cutaneous infection. Skin-resident T cells orchestrate numerous immunological functions that are critically involved in both tissue homeostasis and cutaneous immunity. The impact of chronic ethanol (EtOH) exposure on skin T cells has not previously been examined; given their important role in maintaining the immune barrier function of the skin further study is warranted.Mice were administered EtOH in the drinking water for 12 to 16 weeks. Flow cytometry was used to evaluate impact of EtOH feeding on skin T cell numbers, rates of proliferation, and apoptosis as well as activation marker expression and cytokine production after ex vivo stimulation.Chronic EtOH feeding caused a baseline reduction in dendritic epidermal T cell (DETC) numbers that corresponded with reduced expression of the activation marker JAML following phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Chronic EtOH feeding did not alter total numbers of dermal T cells, but specific subset loss was observed in Foxp3(+) regulatory T cells (Tregs) as well as CD3hi, V?3(+) and CD3int, V?3(-) dermal ?? T cells. EtOH-induced dysfunction in the latter population, which represents prototypical interleukin-17 (IL-17)-producing dermal ??T17s, was made evident by diminished IL-17 production following anti-CD3 stimulation. Additionally, the capacity of lymph node ?? T cells to produce IL-17 following anti-CD3 and PMA/ionomycin stimulation was impaired by chronic EtOH feeding.Chronic EtOH feeding induced defects in both numbers and function of multiple skin T cell subsets. The decreased density and poor responsiveness of DETCs and ??T17 cells in particular would be expected to compromise immune effector mechanisms necessary to maintain a protective barrier and restrict pathogen invasion. These findings demonstrate the sensitivity of skin T cells to EtOH and provide new mechanisms to help explain the propensity of alcoholics to suffer skin infection.

Project description:BackgroundAdaptation to chronic ethanol (EtOH) treatment of rats results in a changed functional state of the liver and greatly inhibits its regenerative ability, which may contribute to the progression of alcoholic liver disease.MethodsIn this study, we investigated the effect of chronic EtOH intake on hepatic microRNA (miRNA) expression in male Sprague-Dawley rats during the initial 24 hours of liver regeneration following 70% partial hepatectomy (PHx) using miRNA microarrays. miRNA expression during adaptation to EtOH was investigated using RT-qPCR. Nuclear factor kappa B (NFκB) binding at target miRNA promoters was investigated with chromatin immunoprecipitation.ResultsUnsupervised clustering of miRNA expression profiles suggested that miRNA expression was more affected by chronic EtOH feeding than by the acute challenge of liver regeneration after PHx. Several miRNAs that were significantly altered by chronic EtOH feeding, including miR-34a, miR-103, miR-107, and miR-122 have been reported to play a role in regulating hepatic metabolism and the onset of these miRNA changes occurred gradually during the time course of EtOH feeding. Chronic EtOH feeding also altered the dynamic miRNA profile during liver regeneration. Promoter analysis predicted a role for NFκB in the immediate-early miRNA response to PHx. NFκB binding at target miRNA promoters in the chronic EtOH-fed group was significantly altered and these changes directly correlated with the observed expression dynamics of the target miRNA.ConclusionsChronic EtOH consumption alters the hepatic miRNA expression profile such that the response of the metabolism-associated miRNAs occurs during long-term adaptation to EtOH rather than as an acute transient response to EtOH metabolism. Additionally, the dynamic miRNA program during liver regeneration in response to PHx is altered in the chronically EtOH-fed liver and these differences reflect, in part, differences in miRNA expression between the EtOH-adapted and control livers at the baseline state prior to PHx.

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Mechanisms by which chronic ethanol feeding impairs the migratory capacity of cutaneous dendritic cells.

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Mechanisms by which chronic ethanol feeding impairs the migratory capacity of cutaneous dendritic cells.

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