ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity

A. FERRARO; J. PANDOLFI; I. SANANEZ; M.C. GANCEDO

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Año: 2016 p. 3287 - 3296

0022-1767

Obesity-induced inflammation is conducted by a metabolic pathway, which eventually causes activation of specialized immune cells andleads to an unresolved inflammatory response within the tissue. For this reason, it is critically important to determine how hypertrophicfat tissue alters T cell balance to drive inflammation. In this study, we identify the purinergic signaling as a novel mechanism driving theadaptive Th17 response in human visceral adipose tissue (VAT) of metabolically unhealthy obese patients. We demonstrate that ATPacting via the P2X7 receptor pathway promotes a Th17 polarizing microenvironment with high levels of IL-1b, IL-6, and IL-17 in VATexplants from lean donors. Moreover, in vitro blockade of the P2X7 receptor abrogates the levels of these cytokines. These findingsare consistent with a greater frequency of Th17 cells in tissue from metabolically unhealthy obese donors, revealed not only by thepresence of a baseline Th17-promoting milieu, but also by the higher expression of steadily recognized Th17 markers, such as RORC,IL-17 cytokine, and IL-23R, in comparison with metabolically healthy obese and lean donors. In addition, we demonstrate that CD39expression on CD4+ effector T cells represents a novel Th17 marker in the inflamed VAT, which also confers protection against ATP-induced cell death. The manipulation of the purinergic signaling might represent a new therapeutic target to shift the CD4+ T cellbalance under inflammatory conditions.