Obesity-driven IL-18 inhibits the suppressive function of FOXP3+ T-regulatory (Treg) cells

Abstract

Abstract We investigated ways by which obesity affects the immune system and promotes inflammation, given that obesity has a high economic and medical impact, worldwide. IL-18 was the only inflammatory marker differing between our colonies of “obese but otherwise healthy” (hHFD) and “obese with low-grade inflammation” (iHFD) mice. All mice gained weight equally, had signs of low-grade inflammation (increased TNF-a, IL-1b and IL-6 mRNA) in adipose tissues, and high plasma leptin levels. The livers of hHFD mice had no inflammatory phenotype despite evidence of steatosis, whereas livers of iHFD mice had increased TNF-a, IL-1b, IL-6 and IL-7 mRNA. Levels of IL-18 were increased in livers and fat of iHFD, but not hHFD mice, and were associated with significant impairment of Treg suppressive function. Addition of IL-18 had significant inhibitory effects on the suppressive function of murine and human Tregs, and Tregs isolated from obese/overweight patients also had impaired suppressive activity. Human Tregs express high levels of IL-18Ra, and downregulate FOXP3 protein but not mRNA, when stimulated in the presence of IL-18. FOXP3 downregulation compromises the FOXP3-regulated gene network, leading to re-activation of pro-inflammatory genes such as IFN-g, IL-2, IL-6 and IL-17, and downregulation of CTLA-4 protein, which is critical for suppressive function. Our preliminary data indicate that IL-18 activates the MyD88 pathway in Tregs and impairs FOXP3 protein stability, possibly by ubiquitination and proteasomal degradation. This may be a physiologically essential tool to dampen Treg function during acute infection and increase the efficiency of immune responses, but has a detrimental effect in obesity-driven low-grade inflammation.