The Role of Transcription Factor PPAR-γ in the Pathogenesis of Psoriasis, Skin Cells, and Immune Cells

Abstract

The peroxisome proliferator-activated receptor PPAR-γ is one of three PPAR nuclear receptors that act as ligand-activated transcription factors. In immune cells, the skin, and other organs, PPAR-γ regulates lipid, glucose, and amino acid metabolism. The receptor translates nutritional, pharmacological, and metabolic stimuli into the changes in gene expression. The activation of PPAR-γ promotes cell differentiation, reduces the proliferation rate, and modulates the immune response. In the skin, PPARs also contribute to the functioning of the skin barrier. Since we know that the route from identification to the registration of drugs is long and expensive, PPAR-γ agonists already approved for other diseases may also represent a high interest for psoriasis. In this review, we discuss the role of PPAR-γ in the activation, differentiation, and proliferation of skin and immune cells affected by psoriasis and in contributing to the pathogenesis of the disease. We also evaluate whether the agonists of PPAR-γ may become one of the therapeutic options to suppress the inflammatory response in lesional psoriatic skin and decrease the influence of comorbidities associated with psoriasis.

Keywords: PPAR-γ; immune cells; psoriasis; skin.

Figure 1

Chemical structures of the thiazolidinediones: A—thiazolidinedion; B—englitazone; C—ciglitazone; D—pioglitazone; E—rosiglitazone, F—troglitazone (the tocopherol group of troglitazone is shown inside the rounded blue rectangle).

Figure 2

Transactivation of PPAR-γ. A—Interactions of agonist with PPAR-γ (shown in red) and 9-cis retinoic acid with RXR (shown in yellow). The activation of PPAR-γ and RXR by their ligands causes conformational changes. These changes cause dissociation of protein repressors and recruitment of activators (not shown). B—Heterodimerization of PPAR-γ and RXR. C—Binding of the heterodimer RXR-PPAR-γ to PPRE on the DNA. DR1 and DR2 are two halves of PPRE separated by a single nucleotide (N).

Figure 3

Transrepression by PPAR-γ. (A) The interaction of PPAR-γ with the RELA/p65 subunit of NFκB (tethering). The ligand-activated heterodimer of PPAR-γ and RXR replaces the transcriptional activator p300 in the complex, with the transcriptional factor NFκB attaching itself to the subunit p65. (B) The competition of PPAR-γ–p300 and AP1–p300 for binding to the promoter of CCND1. The ligand-activated heterodimer of PPAR-γ and RXR forcedly substitutes AP1 in its complex with p300. (C) SUMOlated PPAR-γ stabilizes the repressor complex NCoR–HDAC3–TBL bound to a gene promoter.

Figure 4

Transcriptional activation of the genes involved in polarization of macrophages toward the anti-inflammatory M2 phenotype. Binding of IL4 to the specific receptor (IL4R-α) triggers phosphorylation of the transcription factor STAT6 by JAK1. Phosphorylated STAT6 homodimerizes and then crosses to the nucleus, where it interacts with IL4-sensitive/RGS-insensitive enhancers of the DNA. This interaction recruits the heterodimer of agonist-free PPAR-γ and RXR, which are transcriptional activators. It also causes structural changes in the chromatin, making it accessible for RNA polymerase II and the transcription of genes.

Figure 5

The role of PPAR-γ in the pathogenesis of psoriasis.