Bergenin inhibits γδT17 cell activation to alleviate ulcerative colitis by down-regulating fatty acid oxidation via targeting miR-124-3p.

BACKGROUND

Bergenin, the main active ingredient of Bergenia purpurascens, was previously reported to alleviate dextran sulfate sodium (DSS)-induced colitis in mice. Cytokine IL-17 plays a pivotal role in the development of ulcerative colitis (UC), and γδT17 cells are the primary producers of IL-17 in gut. Whether bergenin functions through inhibiting γδT17 cell activation remains to be identified.

PURPOSE: To investigate the effect of bergenin on γδT17 cell activation and explore the mechanism based on cellular metabolism.

METHODS

Primary γδT cells derived from C57BL/6 mouse spleens were stimulated under γδT17 activation conditions. Flow cytometry, qPCR, and western blot were used to analyze the expression of transcription factors, cytokines, and metabolic enzymes. Fatty acid oxidation (FAO) was assessed through oxygen consumption rate (OCR) detection, and its importance was verified by overexpression of carnitine palmitoyl transferase 1 (CPT1). Histone acetylation at RORγt promoter was detected by chromatin immunoprecipitation (ChIP)-qPCR. Colitis model was constructed by DSS in mice.

RESULTS

In vitro, bergenin concentration-dependently attenuated γδT17 cell activation and preferentially altered FAO during γδT17 cell activation, especially at the early activation stage. CPT1 overexpression markedly diminished the inhibition of bergenin on γδT17 cell activation. Bergenin increased the expression of miR-124-3p targeting CPT1 to downregulate FAO and thereby decreased the acetylation of H3K27 at the RORγt promoter region of γδT17 cells. l-carnitine, an enhancer of FAO, weakened the inhibition of bergenin against γδT17 cell activation and also attenuated its anti-colitis effect.

CONCLUSION

Bergenin exerts anti-UC effect by inhibiting γδT17 cell activation and consequent IL-17 expression. It functions via miR-124-3p/CPT1/acetyl-CoA axis-mediated suppression of histone acetylation at RORγt promoter. The miR-124-3p and FAO are potential targets for therapeutic agents of γδT17 cell activation-related diseases.