Abstract
Alcohol exerts significant immunomodulatory effects on innate and adaptive immune responses, impairing host defense against infections. Gut-mucosa-derived dendritic cells (DCs) traffic to mesenteric lymph nodes (MLNs) through mesenteric lymphatic vessels (MLVs), contributing to intestinal antigen homeostasis. Previously, we demonstrated that acute alcohol administration to male rats induces MLV hyperpermeability resulting in perilymphatic adipose tissue (PLAT) inflammation and insulin signaling dysregulation. We hypothesized that alcohol-induced MLV hyperpermeability can lead to DC leakage to PLAT. DCs promote adipose tissue regulatory T cell (Treg) expansion, and this has been proposed as a mechanism underlying age-associated insulin resistance (IR). The aim of this study was to determine whether chronic alcohol consumption promotes DC leakage to PLAT and results in metabolic dysregulation. Male rats received a Lieber–DeCarli liquid diet containing 36% of calories from alcohol for 10 weeks. Time-matched control animals were pair-fed. PLAT, MLNs, and peripheral blood leukocytes (PBLs) were isolated for flow cytometry analyses. PLAT explants were used for determinations of insulin-induced glucose uptake. Chronic alcohol consumption decreased MLN CD4/CD8 ratio and Treg frequency in PBLs. Alcohol increased the frequency of DCs, CD4 T cells, and Tregs in PLAT. Lastly, alcohol decreased insulin-stimulated glucose uptake in PLAT. Collectively, these findings suggest that alcohol-induced immune cell deviation from the gut–MLN pathway is associated with PLAT immunometabolic dysregulation. Whether this immune cell deviation impacts induction of mucosal immunity warrants further investigation.
Highlights
Alcohol consumption is prevalent in the US, with over 50% of adults over 18 years old being regular drinkers [1]
We have demonstrated that acute alcohol administration to rats leads to mesenteric collecting lymphatic leakage, perilymphatic adipose tissue (PLAT) immune cell recruitment and inflammation, and impairments in insulin signaling in PLAT and not in other adipose depots, including subcutaneous fat (SFAT) [13,14]
To expand our understanding of the interaction of immune macromolecules contained in mesenteric lymphatic vessels (MLVs) with PLAT, this study aimed to investigate the effects of a chronic alcohol diet on PLAT immunometabolism in rodents
Summary
Alcohol consumption is prevalent in the US, with over 50% of adults over 18 years old being regular drinkers [1]. Among the several consequences of acute and chronic alcohol consumption, the immunomodulatory effects of alcohol affecting innate and adaptive immune responses contribute to impaired antimicrobial defense and inflammatory responses throughout the body. Alcohol impairs host response to numerous infections or worsens the effects of disease affecting several organs and tissues [2]. The immune system plays a comprehensive and understated role in adipose tissue and systemic metabolism surveilling and responding to specific metabolic signals through a set of processes termed immunometabolism [3]. Chronic and binge alcohol drinking have been shown to impact the whole body and adipose tissue by impairing insulin-dependent responses and decreasing insulin-stimulated glucose uptake [2,4,5]. The mechanisms underlying alcohol-induced immune cell-mediated metabolic homeostasis in the adipose tissue are unknown
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