Adiponectin/AdipoR1 Axis Promotes IL-10 Release by Human Regulatory T Cells

Abstract

BackgroundAdiponectin is an important immunomodulatory mediator in inflammatory conditions. While we previously showed that adiponectin receptor 1 (AdipoR1) is expressed in murine regulatory T cells (Tregs), its expression in human Tregs remain unknown. Here, we examined the expression of AdipoR1 in human Tregs and whether its ligand, globular adiponectin (gAd) affects the Treg ability to secrete IL-10 and the role of Type 2 (T2) inflammation in such process.MethodsHuman Tregs from peripheral blood were analyzed by flow cytometry for AdipoR1, Helios and IL-10 expression. CD4+ T cells enriched from peripheral blood mononuclear cells (PBMCs) were cultured in the presence or the absence of gAd or the chemical adiponectin receptor agonist, AdipoRon, or in a T2 cytokine milieu. Flow cytometry was then used to assess intracellular IL-10, IL-10 secreting cells, FOXP3 and Helios expression, and phosphorylated p38 MAP kinase (MAPK). IL-10 levels in CD4+ T cell supernatants were quantified by ELISA.ResultsWe found that a subset of human Tregs expressed AdipoR1. Importantly, more Helios- cells expressed AdipoR1 than Helios+ cells. Likewise, there was a higher frequency of IL-10+ cells within Helios- AdipoR1+ Tregs compared to Helios+ AdipoR1+ Tregs. In contrast, the IL-10 mean fluorescence intensity (MFI) was higher in Helios+ AdipoR1+ Tregs compared to Helios-AdipoR1+ Tregs. When human CD4+ T cells were treated with gAd or AdipoRon, a significant increase in IL-10 secretion, FOXP3 expression, and p38 MAPK phosphorylation was observed in Helios- AdipoR1+ Tregs. Interestingly, gAd under T2 cytokine milieu significantly increased the intracellular levels of IL-10, mainly in Helios+ AdipoR1+ Tregs, and IL-10 levels in supernatants of CD4+ T cells.ConclusionsCollectively, our findings suggest that adiponectin/AdipoR1 axis promotes IL-10 release by Tregs, mainly in Helios- Tregs, and the effect was amplified by T2 inflammation in Helios+ Tregs.

Helminth infection modulates number and function of adipose tissue Tregs in high fat diet-induced obesity

“…In contrast, adiponectin stimulates insulin function [ 12 , 58 , 59 ] and sensitivity [ 59 ], and its levels are negatively correlated with waist circumference, visceral fat weight, triglycerides and HDL levels, fast glucose and insulin levels, and also with the development of type 2 diabetes [ 78 – 80 ]. Interestingly, leptin and adiponectin play opposite roles to Treg balance: while leptin inhibits Treg function [ 81 , 82 ], adiponectin promotes regulatory functions, including IL10 production [ 83 ]. IL10 possess various cellular sources, being Tregs a major producer.…”

Adiponectin and Asthma: Knowns, Unknowns and Controversies

“…These effects were not reproduced in another study which showed that the effects of ADPN depend on the polarization of the cell; in M1 macrophages, ADPN triggers the expression of proinflammatory cytokines (IL-6, TNFα, IL-12), whereas in M2 macrophages it induces the expression of IL-10 [35,36] and IL-1 receptor antagonist [37]. IL-10 secretion is further enhanced by ADPN's effects on regulatory T lymphocytes (Tregs) [38].…”

“…Peripheral Tregs express more AdipoR1 than thymus-derived ones. Globular ADPN increases the secretion of IL-10 in peripheral Tregs, particularly in a Th2 milieu [38], in macrophages, monocytes and dendritic cells [37]. In macrophages, IL-10 induces the mRNA expression of the tissue inhibitor of metalloproteinase 1 (TIMP-1) [36].…”

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity

“…Considering this evidence, recent in vivo and in vitro studies have explored the relationship between levels of these adipokines and lung diseases, revealing that leptin and adiponectin can directly regulate lung inflammation and immune function [69,[94][95][96][97]. As a matter of fact, it has been observed that adipoR1 is expressed in immune regulatory T cells (Tregs) in the lungs and modulates the immune response during pulmonary inflammation [69].…”

“…Therefore, the balance between these two cell populations is essential for the regulation of the immune system. In vivo studies on mice showed that activation of adipoR1 in lung Tregs promoted their proliferation and activity, thereby suppressing the immune response and inflammation [95]. However, this mechanism was impaired in obesity due to downregulation of adipoR1 expression, reducing Treg activity and promoting airway inflammation [69].…”