The role of IL-17 in the loss of the anticontractile effect of perivascular adipose tissue and of IL-6 in the polarization of naïve T lymphocytes to the Th17 phenotype during ethanol consumption

• Grant number: 24/15661-7
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2025
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Carlos Renato Tirapelli
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Ethanol consumption is a risk factor for the development of cardiovascular diseases, such as high blood pressure. Ethanol promotes functional and structural changes in the vasculature, in addition to affecting perivascular adipose tissue (PVAT), a biologically active tissue, composed of adipocytes, fibroblasts and cells of the immune system. PVAT has physiological anti-contractile action, and ethanol alters the PVAT phenotype favoring a pro-oxidative and pro-inflammatory phenotype, which is characterized by an increase in the production of reactive oxygen species (ROS), a decrease in the bioavailability of nitric oxide (NO), neutrophil infiltration and an increase in pro-inflammatory cytokines. Furthermore, ethanol consumption increases circulating concentrations of interleukin (IL)-6, a cytokine that is involved in the vascular dysfunction and arterial hypertension induced by ethanol consumption. IL-6 is essential in the polarization process of naïve T lymphocytes to the T helper-17 (Th17) phenotype, in addition to inhibiting polarization to the regulatory T (Treg) phenotype. The Th17 lymphocyte is the main source of IL-17, an interleukin that has important pathophysiological actions and that contributes to the process of vascular dysfunction in arterial hypertension, obesity and diabetes mellitus, as it favors the production of ROS, reduces the bioavailability of NO and favors the vascular infiltration of neutrophils. It is worth mentioning that Th17 lymphocytes and IL-17 are important mediators of the harmful actions of ethanol in different tissues including liver, lung, skin and intestine. However, the relationship between IL-6, Th17 lymphocyte infiltration, IL-17 release, and loss of PVAT anticontractile effect associated with ethanol consumption remains elusive. The hypothesis of the present study is that ethanol consumption will increase circulating concentrations of IL-6, which will favor the polarization of naïve T lymphocytes to the Th17 phenotype in mesenteric lymph nodes while promoting a reduction in the polarization of Treg lymphocytes. Th17 lymphocytes will infiltrate into PVAT where they will release IL-17, which will induce (via IL-17RA) loss of the anti-contractile action of PVAT by mechanisms that involve increased ROS generation (via NADPH oxidase), reduced NO bioavailability and neutrophil infiltration. Taken together, the actions of IL-17 will promote loss of the anticontractile effect of PVAT. The objective of this study is to evaluate the contribution of IL-17 to the change in PVAT phenotype promoted by ethanol consumption, focusing on the production of ROS and decreased NO bioavailability. In addition, the participation of IL-6 in the polarization of lymphocytes T naive to the Th17 phenotype, infiltration of these cells in PVAT and increased production of IL-17 will be verified. For this purpose, male C57Bl6 mice (Wild Type; WT) will be treated with ethanol for 12 weeks. The participation of IL-6 in the polarization of naïve T lymphocytes to Th17 will be evaluated using knockout mice for this cytokine (IL-6-/-; B6.129S6-Il6tm1Kopf). The role of IL-17 in PVAT dysfunction will be evaluated using knockout animals for the IL-17RA receptor (IL-17RA-/-; B6.Cg-Il17ratm2.2Koll/J). Functional (blood pressure, vascular reactivity) and molecular assessments (flow cytometry, ELISA, real-time PCR, Western immunoblotting) will be performed using blood, mesenteric lymph nodes, mesenteric PVAT and mesenteric arterial bed. (AU)