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

Background: Peroxisome proliferator-activated receptor- (PPAR-) γ 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- γ 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- γ 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- γ 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- γ 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- γ by pioglitazone resulted in increased percentages of CD4+ CD25+ Foxp3+ Treg cells and decreased percentages of CD3+ CD4+ IFN- γ + and CD3+ CD4+ IL-4+ cells in the liver and spleen of Schistosoma japonicum -infected mice. In addition, the PPAR- γ 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- γ agonist can promote the expression of Foxp3; however, the inhibitor of PPAR- γ weakened the expression of Foxp3 by modifying the coexpression of Foxp3 and PPAR- γ .

Conclusions: Our study reveals a previously unrecognized role for PPAR- γ /Foxp3 signaling in regulating the immunopathology that occurs during Schistosoma infection through induction of Treg cells.