The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Abstract

Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

“…A selective inhibitor for soluble TNF receptors was beneficial for the treatment of mycobacterial infections through neutralization of excessive TNF (49). Extensive studies have reported the roles of PPAR-a agonists in the modulation of innate and adaptive immune responses (50)(51)(52). These data thus indicate that PPAR-a agonists may protect hosts against excessive inflammatory responses during mycobacterial infection to promote a balanced inflammatory response.…”

A novel Pseudolaric acid B derivative, Hexahydropseudolaric acid B, exterts an immunomodulatory effect in vitro/in vivo evaluation

“…Peroxisome proliferator-activated receptors (PPARs), which include PPAR-α, PPAR-β/δ, and PPAR-γ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, metabolism, and mediating the immune responses of T and B cells, among which PPAR-γ has been studied more extensively in both mouse and human T cells than the other PPAR subfamilies (Choi and Bothwell, 2012). Recent reports suggest that PPAR-γ is a major orchestrator of the unique properties of Tregs.…”

“…Moreover, PPAR-γ deficiency leads to decreased numbers of CD4 þ Foxp3 þ T cells, suggesting that PPAR-γ plays an important role in Tregs development (Choi and Bothwell, 2012). Previous study has demonstrated that PAB could function as an agonist of PPAR-γ via stimulating PPAR-dependent gene transcriptions (Jaradat et al, 2002).…”

Peroxisome Proliferator-Activated Receptor α in Lipid Metabolism and Atherosclerosis

“…A number of PPARα ligands have been identified so far, which predominantly include endogenous and synthetic ligands. The important endogenous ligands of PPARα include essential fatty acids and their derivatives, such as eicosanoids, 8S-hydroxyeicosatetraenoic acid, and leukotriene B4 [15]. Another group of endogenous ligands consists of lipid metabolites from saturated or unsaturated fatty acids.…”