PPARα suppresses Th17 cell differentiation through IL-6/STAT3/RORγt pathway in experimental autoimmune myocarditis

Family members of peroxisome proliferator-activated receptors (PPARs), such as PPAR gamma, have been shown to be effective in regulating T helper 17 (Th17) cell differentiation. However, whether PPAR alpha, another important family member of PPARs, contributes to Th17 cell differentiation remains controversial. In the present study, we show that PPAR alpha may be a negative regulator of Th17 cell differentiation. In CD4(+) T cells from PPAR alpha knockout mice, PPAR alpha deficiency enhances IL-17 and IL-6 levels and promotes Th17 cell differentiation. In contrast, in CD4(+) T cells from wild type mice, PPAR alpha activation suppresses Th17 cell differentiation. Furthermore, IL-6 neutralizing antibody dose-dependently reduces the activity of STAT3 and down-regulates the protein expression of ROR gamma t in CD4(+) T cells from PPAR alpha knockout mice but has no effect on that of wild type mice. On the other hand, in isolated CD4(+) T cells from experimental autoimmune myocarditis (EAM) rats, PPAR alpha agonist Fenofibrate decreased the expression of IL-17 and ROR gamma t, increased the expression of Foxp3, while PPAR alpha antagonist MK886 reversed these effects. Importantly, in vivo activation of PPAR alpha ameliorates EAM by suppressing Th17 cell differentiation through reducing the expression of ROR gamma t and phosphorylated STAT3 that are upregulated in EAM hearts. These results imply that PPAR alpha suppresses Th17 cell differentiation through IL-6/STAT3/ROR gamma t signaling pathway and suggest that PPAR alpha may become a molecular target for treating autoimmune myocarditis.