TH9 cells, a subpopulation of TH2 cells, are crucial mediators of allergic skin inflammation. They are characterized by expression of IL-9/IL-9R and rely on the transcription factor PPARγ for full effector function. The functional role of PPARγ in TH9 cells, however, remains unknown. Pathway analysis of RNA-seq data from PPARγ-inhibited TH9 cells revealed concerted downregulation of genes associated with T cell activation, glucose metabolism, and aerobic glycolysis. Accordingly, TH9 cells featured a higher glycolytic activity as compared to TH1 and TH2 cells. In turn, impairment of glycolysis led to downregulation of IL-9, but not IL-13 expression, thus emulating the effects of PPARγ antagonism on cytokine production. Conversely, enhancing glycolytic activity by increasing glucose availability increased IL-9 levels, while leaving IL-13 expression unchanged. Mechanistically, PPARγ- and glycolysis-dependent regulation of IL-9 expression was mediated through mTORC1. Collectively, these observations indicated a dichotomous regulatory role of glycolytic activity on IL-9 and IL-13 expression in activated TH9 cells that is dependent on PPARγ-regulated glycolysis and mediated via mTORC1. In vitro and ex vivo studies on samples of allergic contact dermatitis indicated that this PPARγ/mTORC1/IL-9 pathway was active in pTH2 cells in human skin inflammation. Additionally, we found that tissue glucose levels were dynamically regulated in acute allergic skin inflammation, suggesting that in situ glucose availability might be linked to distinct immunological signals in vivo. In summary, our data propose that PPARγ is a positive regulator of glucose metabolism in TH9 cells and that IL-9 expression is specifically dependent on tissue availability of glucose and cellular metabolic activity. These findings highlight a novel link between the metabolic environment in the tissue during inflammation and type 2-driven skin inflammation.
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