Peroxisome Proliferator-Activated Receptor-γ-Deficient Heterozygous Mice Develop an Exacerbated Neural Antigen-Induced Th1 Response and Experimental Allergic Encephalomyelitis

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that regulates cell growth, differentiation, and homeostasis. PPARγ agonists are potent therapeutic agents for type 2 diabetes, obesity, and inflammation. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis. We have shown recently that PPARγ agonists inhibit EAE by blocking IL-12 production, IL-12 signaling, and neural Ag-induced Th1 differentiation. In this study, we show that the PPARγ-deficient heterozygous mice develop an exacerbated EAE with prolonged clinical symptoms than the wild-type littermates, following immunization with myelin oligodendrocyte glycoprotein (MOG) p35–55 peptide. The exacerbation of EAE in PPARγ+/− mice associates with an increased expansion of CD4+ and CD8+ T cells and expression of CD40 and MHC class II molecules in response to MOGp35–55 Ag. The PPARγ+/− mice also showed an increase in T cell proliferation and Th1 response to MOGp35–55 Ag than the wild-type littermates. These findings suggest that PPARγ be a critical physiological regulator of CNS inflammation and demyelination in EAE and perhaps multiple sclerosis and other Th1 cell-mediated autoimmune diseases.