In obese hypertensives cholecalciferol inhibits circulating TH17 cells but not macrophage infiltration on adipose tissue

Abstract

In arterial hypertension, increased Th17 cells and reduced Tregs are the hallmarks of immunological dysfunction and the basis for the investigation of immunomodulatory drugs. Although cholecalciferol is not a primary immunomodulator, it has recognized action on immune cells, leading us to hypothesise if cholecalciferol can induce a more tolerogenic phenotype in obese hypertensives. In a phase-2, single-centre, randomised, open, 24-week trial, we assigned adults with obesity-associated hypertension and vitamin D deficiency to receive usual therapy plus 50,000 IU/week of cholecalciferol or usual therapy alone. The primary endpoint was the percentual variation in T CD4⁺, T CD8⁺, Tregs, and Th17 cells. Secondary endpoints included the percentual variation in Th1, Tc1, Tc17, and monocytes and variation in the number of perivascular and non-perivascular macrophages, T CD4⁺ and T CD8⁺ lymphocytes in subcutaneous abdominal adipose tissue. A control group of 12 overweight normotensives was also evaluated for peripheral immune cells. A total of 36 obese hypertensives were randomised, 18 in each group. In comparison with normotensive controls, hypertensives presented higher percentages of T lymphocytes (p = 0.016), Tregs (p = 0.014), and non-classical monocytes (p < 0.001). At week 24, Th17 cells increased in control group (p = 0.017) but remained stable in cholecalciferol group. For Tregs, downregulation towards the values of normotensive controls was observed (p = 0.003), and in multivariate analysis, an increased loading in the setting of the cells of adaptive immunity observed (eigenvalue 1.78, p < 0.001). No changes were documented for monocytes. In adipose tissue, a baseline negative correlation between vitamin D and perivascular macrophages was observed (r = -0.387, p = 0.024) that persisted in the control group (r = -0.528, p = 0.024) but not in the cholecalciferol group, which presented an increase in non-perivascular macrophages (p = 0.029) at week 24. No serious adverse events were reported for all the participants. In this trial, we found that supplementation with cholecalciferol interfered with peripheral and adipose tissue immune cell profile, downregulating peripheral Th17 cells, but increasing the number of infiltrating subcutaneous adipose tissue macrophages. (Funded by Núcleo Estudos Hipertensão da Beira Interior; EudraCT number: 2015-003910-26).

Keywords: Adipose tissue; Cholecalciferol; Hypertension; Macrophages; Th17; Treg-regulatory.