Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation

Abstract

Obesity is a major risk factor for psoriasis, but how obesity disrupts the regulatory mechanisms that keep skin inflammation in check is unclear. Here, we found that skin was enriched with a unique population of CD4⁺Foxp3⁺ regulatory T (Treg) cells expressing the nuclear receptor peroxisome proliferation-activated receptor gamma (PPARγ). PPARγ drove a distinctive transcriptional program and functional suppression of IL-17A⁺ γδ T cell-mediated psoriatic inflammation. Diet-induced obesity, however, resulted in a reduction of PPARγ⁺ skin Treg cells and a corresponding loss of control over IL-17A⁺ γδ T cell-mediated inflammation. Mechanistically, PPARγ⁺ skin Treg cells preferentially took up elevated levels of long-chain free fatty acids in obese mice, which led to cellular lipotoxicity, oxidative stress, and mitochondrial dysfunction. Harnessing the anti-inflammatory properties of these PPARγ⁺ skin Treg cells could have therapeutic potential for obesity-associated inflammatory skin diseases.

Keywords: IL-17A; PPARγ; Treg; free fatty acid; high-fat diet; immunometabolism; obesity; psoriasis; skin; γδ T cell.