Exogenous Annexin 1 inhibits Th17 cell differentiation induced by anti-TNF treatment via activating FPR2 in DSS-induced colitis

Anti-TNF treatment has played a vital role in treating Inflammatory Bowel Disease (IBD). However, T helper 17 (Th17) cells, which facilitate the development of IBD, are not reduced and even increased during anti-TNF clinical studies. Therefore, inhibition of Th17 cells is of great significance for improving anti-TNF treatment.DSS-induced colitis mice were treated with the anti-TNF nanobody V7 and ANX1, and the variation in intestinal Th17 cells and DCs was estimated by flow cytometry. RAW264.7 cells were used to study the differentiation mechanism of Th17 cells from colon and mesenteric lymphocyte nodes (mLN).Intestinal Th17 cells increased after DSS-induced colitis was well treated with V7 (10 mg/kg). Th17 cell differentiation induced by V7 was accounted for by the accumulation of the V7-TNF complex, which was phagocytized by lamina propria (LP) DCs and induced the upregulation of MHCII. V7-TNF complex phagocytized RAW264.7 (CPR) was constructed and directly induced Th17 cell differentiation in colon LPLs and mLN in vitro. After knocking down CIITA in RAW264.7 cells, the induction was inhibited. Furthermore, Annexin 1 (ANX1) was upregulated and activated the FPR2-STAT3 pathway to inhibit the differentiation of Th17 cells. Then, animal assay demonstrated that ANX1 (500 μg/kg) enhanced the therapeutic effect of V7 (10 mg/kg) on DSS-induced colitis accompanied by a decrease in Th17 cells in mLN and colon.The differentiation of Th17 cells induced by V7 was mediated by phagocytosis of V7-TNF complexes by DCs and regulated by exogenous ANX1 via activation of the FPR2-STAT3 pathway. The combination of V7 and ANX1 presented a better therapeutic effect than monotherapy on DSS-induced colitis.