Bile acid conditioned Dendritic cells through FXR and specialize T cell function in the ileum

Abstract

Abstract The accumulation of locally-reabsorbed bile acids (BAs) is suggested to contribute to the development of terminal ileitis. Our previous data showed nuclear receptor Constitutive Androstane Receptor (CAR) can directs T cell adaptation to BAs in the ileum by promoting the IL-10 producing Tr1 cells to prevent ileitis. Still, the mechanisms by which BA activate CAR in ileal T cells is not known. As CAR is not recognized as a BA sensor, its activation in ileal T cells may involves indirect pathways, such as dendritic cells (DCs). Farnesoid X receptor (FXR), a direct primary BA sensor, is highly expressed in both human and mouse DCs. Therefore, we hypothesized that BA-sensing by mucosal DCs through FXR may condition mucosal T cells in the ileum to upregulate CAR and to enforce anti-inflammatory T cell functions. Our result indicated WT DCs exposed to direct FXR agonist, chenodeoxycholic acid (CDCA), displayed increased production of IL-23a and decreased IL-6. While, CD4 +T cells cocultured with CDCA-treated DCs displayed increased CAR/Nr1i3, and its targets, cMyc and MDR1. Importantly, these observations were diminished in DCs from FXR −/−mice. In addition, when FXR is depleted in DC (CD11cCreFXR fl/fl, FXR ΔDC), the DC migration in the intestine is deficient, with low expressions of CCL19, CCR9 and less CD11c +CD11b −CD103 +MHCII +migratory DC population in the mesenteric lymph nodes. Meanwhile, the FXR ΔDCmice failed to promote CAR/Nr1i3as well as IL10in T cells. Furthermore, FXR −/−RAG2 −/−mice developed severe ileitis after engrafted with WT naïve T cell. These results suggest that FXR specializes intestinal DC and T cell function in the ileum. Collectively, these studies will shed new light on the understanding and treatment of ileitis in patients.