T helper (Th) 17 cells highly contribute to the immunopathology of rheumatoid arthritis. Morin, a natural flavonoid, owns well anti-arthritic action but unclear effect on Th17 differentiation. This study tried to solve this issue and explore the mechanisms in view of cellular metabolism. Naïve CD4+ T cells were treated with anti-CD3/CD28 along with Th17-inducing cytokines. Morin was shown to block Th17 differentiation without affecting cell viability even when Foxp3 was dampened. The mechanisms were ascribed to the limited fatty acid synthesis by restricting FASN transcription, as indicated by metabolomics analysis, nile red staining, detection of triglycerides, FASN overexpression, and addition of palmitic acid. Moreover, morin had slight effect on cell apoptosis and protein palmitoylation during Th17 differentiation, but blocked the binding of RORγt to promoter and CNS2 region of Il17a gene. Oleic acid rescued the inhibition of morin on RORγt function, and Th17-inducing cytokines could not induce RORγt function in SCD1-defficient cells, suggesting that oleic acid but not palmitic acid was the direct effector in the action of morin. Then, PPARγ was identified as the target of morin, and GW9662 or PPARγ CRISPR/Cas9 KO plasmid weakened its above-mentioned effects. The transrepression of FASN by morin was owing to physical interaction between PPARγ and Sp1, and the importance of Sp1 in Th17 differentiation was confirmed by siSp1. Finally, the effects and mechanisms for morin-dampened Th17 responses were confirmed in collagen-induced arthritis (CIA) mice. Collectively, morin inhibited Th17 differentiation and alleviated CIA by limiting fatty acid synthesis subsequent to PPARγ activation.
Keywords: Collagen-induced arthritis; Fatty acid synthesis; Morin; PPARγ; Th17 differentiation.
© 2022. The Author(s), under exclusive licence to Springer Nature B.V.