Cytochrome P450 1B1 directs pathogenic-Th17 cell generation and autoimmune disease by maintaining cellular redox homeostasis and mitochondrial function

Th17 cells are heterogenous. Pathogenic Th17 cells induced by IL-23, have been well implicated in inflammatory bowel disease (IBD), while the underlying mechanisms remain unclear. Here, we revealed that cytochrome P450 1B1 (CYP1B1) is specifically upregulated in mice and human colitis disease. With CYP1B1 knockout mice, we found that CYP1B1 specifically promoted IL-6+IL-1b+IL-23 induced pathogenic-Th17 cells while has no effect on TGFb1+IL-6-induced homeostatic Th17 cells. CYP1B1 deficiency significantly ameliorated disease severity in both DSS-induced colitis and colitis-associated colorectal cancer (CAC) models, and impaired pTh17 responses in vivo. Additionally, CYP1B1 deficiency in T cells disrupted glutathione/ROS homeostasis, leading mitochondrial dysfunction and apoptosis by pTh17 cells. ROS elimination by NAC or ectopically GSS expression increased mitochondria fitness and promoted pTh17 cell generation. Taking together, our findings uncover a CYP1B1-ROS-mitochonrial axis in driving pTh17 cell generation and proinflammatory function, interfering this hub may be benefit for pTh17 cell-related immunopathology.