Abstract
This study aimed to investigate whether activation of PPARγ regulates M1/M2 macrophage polarization to attenuate dextran sulfate sodium salt (DSS)-induced inflammatory bowel disease (IBD) via the STAT-1/STAT-6 pathway in vivo and in vitro. We first examined the effect of PPARγ on macrophage polarization in LPS/IFN-γ-treated M1 RAW264.7 cells and IL-4/IL-13-treated M2 RAW264.7 cells. Then, 40 male C57BL/6 mice were randomly divided into five groups: the Sham, IBD, IBD + fludarabine (FLU), IBD + IL-4, and IBD + pioglitazone (PI) groups. The mice received 2.5% DSS in their drinking water for 7 days and then received regular water for 2 days to establish the experimental IBD murine model. The mice in the IBD + FLU, IBD + IL-4, and IBD + PI groups were intraperitoneally injected with FLU, IL-4, and PI, respectively, for 9 days. Clinical symptoms, intestinal barrier function, macrophage polarization, PPARγ, and the STAT-1/STAT-6 pathway were analyzed. Activation of PPARγ decreased M1 polarization marker expression and STAT-1 phosphorylation and increased M2 polarization marker expression and STAT-6 phosphorylation in RAW264.7 cells. Activation of PPARγ attenuated disease symptoms, such as weight loss, diarrhea, and bloody stool. Histological analysis revealed that PI treatment reduced inflammatory cell infiltration, restored the mucosal architecture, and improved the expression of tight junction proteins. Moreover, the activation of PPARγ decreased the expression of iNOS and increased the expression of Arg-1, Fizz 1, and Ym 1 by inhibiting STAT-1 phosphorylation and promoting STAT-6 phosphorylation in mice with DSS-induced IBD. Activation of PPARγ regulates M1/M2 macrophage polarization to attenuate DSS-induced IBD via the STAT-1/STAT-6 pathway in vivo and in vitro.