PPAR- γ Agonist Alleviates Liver and Spleen Pathology via Inducing Treg Cells during Schistosoma japonicum Infection.

Background. Peroxisome proliferator-activated receptor-(PPAR-) gamma plays critical roles in human metabolic disorders and has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Regulatory T cells (Tregs), which express high levels of PPAR-gamma protein, have the ability to maintain immune tolerance to self-antigens and regulate immune response to Schistosoma infection. However, mechanisms involved in the resolution of these responses are elusive. Methods. Liver and spleen tissue samples in Schistosoma japonicum-infected mice after administration of pioglitazone (a PPAR-gamma agonist) were collected. The hepatic and splenic pathologies were detected by H&E and Masson staining. The percentages of Th1/2 and Treg cells in the liver and spleen of each mouse were determined using flow cytometry. Levels of gene expression of PPAR-gamma and Foxp3 in tissues or cells were determined using real-time PCR (RT-PCR). Macrophages were treated with pioglitazone in vitro or cocultured with normal purified CD4(+) T cells for detecting Treg cells by flow cytometry. The interactions of PPAR-gamma with Foxp3 in CD4+ T cells were detected by coimmunoprecipitation. Results. Administration of pioglitazone resulted in the prevention of the development of hepatic and splenic pathologies. Activation of PPAR-gamma by pioglitazone resulted in increased percentages of CD4(+)CD25(+)Foxp3(+) Treg cells and decreased percentages of CD3(+)CD4(+)IFN-gamma(+) and CD3(+)CD4(+)IL-4(+) cells in the liver and spleen of Schistosoma japonicum-infected mice. In addition, the PPAR-gamma agonist can induce Treg cells in vitro directly or by modulating the macrophage's function indirectly. Furthermore, through interaction with Foxp3 in CD4(+) T cells, the PPAR-gamma agonist can promote the expression of Foxp3; however, the inhibitor of PPAR-gamma weakened the expression of Foxp3 by modifying the coexpression of Foxp3 and PPAR-gamma. Conclusions. Our study reveals a previously unrecognized role for PPAR-gamma/Foxp3 signaling in regulating the immunopathology that occurs during Schistosoma infection through induction of Treg