Regulation of the mucosal phenotype in dendritic cells by PPARγ: role of tissue microenvironment

Expression of PPAR in myeloid dendritic cells contributes to development of mucosal phenotype and function in the intestine and lung. Mucosal DCs play a critical role in tissue homeostasis. Several stimuli can induce a mucosal phenotype; however, molecular pathways that regulate development of mucosal DC function are relatively unknown. This study sought to determine whether PPAR contributes to the development of the mucosal phenotype in mouse DCs. Experiments demonstrated that PPAR activation in BMDCs induced an immunosuppressive phenotype in which BMDCs had reduced expression of MHC class II and costimulatory molecules, increased IL-10 secretion, and reduced the ability to induce CD4 T cell proliferation. Activation of PPAR enhanced the ability of BMDC to polarize CD4 T cells toward iTregs and to induce T cell expression of the mucosal homing receptor, CCR9. Activation of PPAR increased the ability of BMDCs to induce T cell-independent IgA production in B cells. BMDCs from PPAR(DC) mice displayed enhanced expression of costimulatory molecules, enhanced proinflammatory cytokine production, and decreased IL-10 synthesis. Contrary to the inflammatory BMDC phenotype in vitro, PPAR(DC) mice showed no change in the frequency or phenotype of mDC in the colon. In contrast, mDCs in the lungs were increased significantly in PPAR(DC) mice. A modest increase in colitis severity was observed in DSS-treated PPAR(DC) mice compared with control. These results indicate that PPAR activation induces a mucosal phenotype in mDCs and that loss of PPAR promotes an inflammatory phenotype. However, the intestinal microenvironment in vivo can maintain the mucosal DC phenotype of via PPAR-independent mechanisms.