The role of peroxisome proliferator-activated receptors (PPAR) in immune responses

Abstract

Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors of nuclear hormone receptor superfamily that regulate energy metabolism. Currently, three PPAR subtypes have been identified: PPARα, PPARγ, and PPARβ/δ. PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery and oxidative phosphorylation (OXPHOS) and regulation of energy homeostasis. In contrast, PPARγ is more important in lipogenesis and lipid synthesis, with highest expression levels in white adipose tissue (WAT). In addition to tissues regulating whole body energy homeostasis, PPARs are expressed in immune cells and have an emerging critical role in immune cell differentiation and fate commitment. In this review, we discuss the actions of PPARs in the function of the innate and the adaptive immune system and their implications in immune-mediated inflammatory conditions.

Keywords: Inflammation; Metabolism; Myeloid cells; PPAR; T cells.

Figure 1.. PPAR structure and mechanism of action.

(A) All PPARs share the basic structural of the most nuclear receptors, consisting of four functional domains named A/B, C, D and E/F. The N-terminal A/B domain contains a ligand-independent activation function 1 (AF-1). The central DNA binding domain (DBD) or C domain is a conserved domain, composed of two zing fingers, and is responsible for the binding of PPAR to the peroxisome proliferator response element (PPRE) in the promoter of target genes. The D domain is a docking site for various cofactors. The E domain or ligand-binding domain (LBD) binds a variety of endogenous or exogenous lipophilic ligands and provides ligand specificity. Recruitment of PPAR cofactors that participate in the transcription process is mediated by the ligand-dependent activation function-2 (AF-2), located in the E/F domain. (B) Ligand binding promotes conformational changes that enable the interaction with co-activator complexes. The full transcriptional activity of PPARs requires binding of cognate lipid ligands, heterodimerization with another nuclear receptor (retinoid-X receptor, RXR), interaction with a number of transcriptional coactivators, and binding of the complex to PPAR response elements (PPREs) in the promotor of target genes. (FA, fatty acid)

Figure 2.. PPARs regulate macrophage polarization and function.

Signals mediated via PPARs regulate the differentiation and function of macrophages and dendritic cells.

Figure 3.. PPARs regulate T cell differentiation and function.

Signals mediated via PPARs regulate the development, differentiation and function of T cells.