Regulation of the Mucosal Phenotype in Dendritic Cells by PPARγ: Role of Tissue Microenvironment
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 PPARγ contributes to the development of the “mucosal” phenotype in mouse DCs. Experiments demonstrated that PPARγ 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 PPARγ 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 PPARγ increased the ability of BMDCs to induce T cell‐independent IgA production in B cells. BMDCs from PPARγΔDC mice displayed enhanced expression of costimulatory molecules, enhanced proinflammatory cytokine production, and decreased IL‐10 synthesis. Contrary to the inflammatory BMDC phenotype in vitro, PPARγΔDC mice showed no change in the frequency or phenotype of mDC in the colon. In contrast, mDCs in the lungs were increased significantly in PPARγΔDC mice. A modest increase in colitis severity was observed in DSS‐treated PPARγΔDC mice compared with control. These results indicate that PPARγ activation induces a mucosal phenotype in mDCs and that loss of PPARγ promotes an inflammatory phenotype. However, the intestinal microenvironment in vivo can maintain the mucosal DC phenotype of via PPARγ‐independent mechanisms.
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These studies were funded by a grant from the Crohn's and Colitis Foundation of America. We thank the UK Flow Cytometry & Cell Sorting Core Facility, which is supported, in part, by the Office of the Vice President for Research, the Markey Cancer Center, and a National Cancer Institute Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center.
The online version of this paper, found at www.jleukbio.org, includes supplemental information.
Tuna, Halide; Avdiushko, Rita G.; Sindhava, Vishal J.; Wedlund, Leia; Kaetzel, Charlotte S.; Kaplan, Alan M.; Bondada, Subbarao; and Cohen, Donald A., "Regulation of the Mucosal Phenotype in Dendritic Cells by PPARγ: Role of Tissue Microenvironment" (2014). Microbiology, Immunology, and Molecular Genetics Faculty Publications. 127.