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

BACKGROUND

Peroxisome proliferator-activated receptor- (PPAR-) 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- protein, have the ability to maintain immune tolerance to self-antigens and regulate immune response to infection. However, mechanisms involved in the resolution of these responses are elusive.

METHODS

Liver and spleen tissue samples in -infected mice after administration of pioglitazone (a PPAR- 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- and Foxp3 in tissues or cells were determined using real-time PCR (RT-PCR). Macrophages were treated with pioglitazone or cocultured with normal purified CD4 T cells for detecting Treg cells by flow cytometry. The interactions of PPAR- 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- by pioglitazone resulted in increased percentages of CD4CD25Foxp3 Treg cells and decreased percentages of CD3CD4IFN- and CD3CD4IL-4 cells in the liver and spleen of -infected mice. In addition, the PPAR- agonist can induce Treg cells directly or by modulating the macrophage's function indirectly. Furthermore, through interaction with Foxp3 in CD4 T cells, the PPAR- agonist can promote the expression of Foxp3; however, the inhibitor of PPAR- weakened the expression of Foxp3 by modifying the coexpression of Foxp3 and PPAR-.

CONCLUSIONS

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