Immunometabolic consequences of alcohol-induced mesenteric lymphatic dyshomeostasis

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Abstract The primary purpose of this Ruth L. Kirschstein NRSA F30 application is to provide the groundwork that will prepare the applicant for an academic medical career. Much of the applicant’s career development will come from work in alcohol comorbidity-related research. Alcohol is the most abused substance in the United States with about one-quarter of the adult population partaking in heavy and/or binge drinking. Chronic alcohol consumption also disrupts glucose homeostasis and is associated with the development of insulin resistance. 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. Results from our previous studies suggest that alcohol-induced mesenteric lymphatic leakage and subsequent perilymphatic adipose tissue inflammation may be a primary event in the development of systemic immunometabolic dysregulation seen in chronic alcohol use. Previously our lab has demonstrated that chronic alcohol induced lymphatic leakage, increased CD3+ and CD4+ T cells, fTregs, and IL-6 in PLAT. Our studies have also shown that chronic alcohol led to decreased insulin-stimulated glucose uptake in PLAT. We speculate that cells or molecules leaking from lymphatic vessels into PLAT stimulate fTreg expansion and lead to PLAT metabolic dysregulation. Taken together, published and preliminary data support the hypothesis that lymph contents from alcohol-treated animals disrupt PLAT immune and metabolic homeostasis through fTreg expansion. The proposed study will employ a wide variety of techniques to test the hypothesis using three specific aims: (1) Lymph from alcohol-treated animals will expand FOXP3+ fTregs in naïve PLAT explants via IL33/ST2 signaling pathway, (2) alcohol-induced fTreg expansion contributes to metabolic dysregulation in PLAT, and (3) alcohol-induced PLAT metabolic dysregulation is associated with systemic metabolic consequences. Findings from the proposed studies will provide insight on the deleterious effects of alcohol-associated lymph leakage and how its constituents impact PLAT immune cell milieu, specifically fTregs, contributing to development of PLAT IR and potentially systemic IR. With a strong mentoring team committed to developing a well-rounded physician scientist, completion of the proposed training plan will ensure that the applicant is ready to embark on a career in academic medicine.