Regulation of Immune Responses and Autoimmune Encephalomyelitis by PPARs

Abstract

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in regulating inflammation as well as lipid metabolism. The PPAR subfamily has been defined as PPARα, PPARβ/δ, and PPARγ, each with different ligands, target genes, and biological roles. PPARs regulate the expression of target inflammatory genes through mechanisms involving both transactivation and transrepression. The anti-inflammatory properties of PPAR agonists have led to the investigation of PPAR functions in regulating autoimmune encephalomyelitis. This paper will summarize some of the general mechanisms by which PPARs regulate inflammatory gene expression and focus on the recent advances of PPAR regulation of autoimmune encephalomyelitis.

Figure 1

Regulation of autoimmune encephalomyelitis by PPAR agonists. CD4 T cells differentiate into different types of T effector cells in the periphery in response to different pathogenic microorganisms as a result of recognition of these organisms by the innate immune system. The IL-12-driven Th1 cell subset mainly produces IFN-γ, IL-2, and GM-CSF and plays an essential role in mediating disease. The Th2 cell subset produces IL-4, IL-5, and IL-13, which are associated with amelioration of EAE and remission in MS. The IL-23-driven Th17 cells have also been shown to be critical in the development of autoimmune diseases. PPAR agonists have been shown to suppress autoimmune encephalomyelitis by regulating the function of both immune cells and CNS-resident cells, including inhibiting Th1 and Th17 differentiation, promoting Th2 differentiation, inhibiting inflammatory cytokine production by microglia and astrocytes, and increasing the number of myelin-producing OLs. Increased expression is indicated by green arrow and decreased expression shown by red blockade.