The prevalence of PPARs in tissues depends on their role in the metabolism of resident cells. In healthy epidermis, the prevalent form of PPAR is PPAR-β/δ because PPAR-β/δ plays a significant role in the maintenance of the skin permeability barrier and the biogenesis of lipids. The epidermal keratinocytes also express some PPAR-α and even less PPAR-γ ^[1][107]. In differentiating keratinocytes, the expression of PPAR-β/δ does not change. At the same time, the levels of PPAR-α and -γ mRNAs increase. Immunostaining for PPAR-γ in keratinocytes is visible in the nucleus and prenuclear region ^[2][108]. In the basal layer of healthy epidermis, the expression of PPAR-γ is almost undetectable ^[3][109]. During the terminal differentiation, the level of PPAR-γ increases 5-fold, peaking in the suprabasal layer ^[4][5][110,111]. The expression of PPAR-γ is also robust in the hair matrix keratinocytes, dermal papilla cells, the inner root sheath of the hair follicle ^[6][112], and sebocytes ^[7][113].

In the lesional psoriatic epidermis, the expression of PPAR-α and -γ is decreased compared to a healthy control. In contrast, the expression of PPARβ⁄δ increases due to the developing inflammatory response ^[8][114]. Psoriasis patients with multiple sclerosis, diabetes, and hypertension have significantly less PPAR-γ compared to the others ^[5][111]. There are also significant correlations of immunostained PPAR-γ in the skin and HDL (r = 0.376, p = 0.003), PASI (r = −0.591, p < 0.001), BMI (r = −0.312, p = 0.001), and blood glucose levels (r = −0.546, p < 0.001). In this regard, some authors ^[5][111] suggested that the reduction of PPAR-γ characterizes the metabolic state of psoriatic patients. Moreover, they proposed using PPAR-γ agonists as an adjuvant therapeutic tool to treat psoriasis patients with multiple sclerosis.

According to the studies performed on mice, either overexpression of PPAR-γ or its activation by agonists may potentially produce variable beneficial effects on the skin (see below). By shifting the balance between differentiation and proliferation toward differentiation, they normalize the terminal differentiation of epidermal keratinocytes and decrease their proliferation rate. The activation of PPAR-γ also modulates the biological effects of infiltrated immune cells and decreases the permeability of dermal microcapillaries. It also reduces the inflammatory response and improves the functioning of the skin barrier. Treatment of animals and cultured cells with agonists of PPAR-γ (troglitazone, rosiglitazone, pioglitazone, and BP-1107) decreases the proliferation rate of epidermal keratinocytes ^[2][9][10][108,115,116]. The antiproliferative effect is fully reversible and removes the used TZD from the culture medium ^[9][10][115,116]. The antiproliferative effects of PPAR-γ agonists are faster in recovering epidermis with a disrupted skin barrier ^[11][117]. For reference, TZDs activate the receptor at significantly lower concentrations than needed to inhibit cell proliferation. Thus, reswearchers are likely dealing with two separate phenomena. The first is the activation of PPAR-γ and the second is the activation of another PPAR by the same agonist with a lower affinity (rev. in ^[12][118]).

Downstream, the antiproliferative signaling of PPAR-γ agonists changes the expression of genes controlling the cell division. Due to transrepression, the expression of cyclins E/CCNE1 and D1/CCND1 decreases and their accumulation slows down ^[13][119]. Contrarily, the genes of cyclin-dependent kinase inhibitors p21 (CDKN1A) and p27 (CDKN1B) become induced due to transactivation ^[14][120]. These changes caused by the activation of PPAR-γ lead to the cell cycle arrest in the G₁ phase. In addition to the specific effects, TZDs also promote the phosphorylation of the eukaryotic initiation factor 2 (E2F). The phosphorylation of E2F prevents its binding to the DNA and reduces its transcriptional activity ^[15][121].

Topical treatment of healthy murine skin with agonists of PPAR-γ such as ciglitazone, troglitazone, and GI262570 accelerates the recovery of the disrupted skin barrier ^[11][117]. The treatment normalizes its functioning by improving the biosynthesis of cholesterol and ceramides ^[16][122]. The named agonists also induce the expression of cholesterol sulfotransferase type 2B1β (SULT2B1β) needed for the biosynthesis of cholesterol sulfate. The sulfotransferase plays a crucial role in desquamation of the cornified cells ^[17][123]. In turn, cholesterol sulfate induces the genes required to support the skin barrier. The agonists of PPAR-γ also induce the genes controlling the terminal differentiation of epidermal keratinocytes, namely involucrin (IVL), loricrin (LOR), transglutaminase-1 (TGM1), and filaggrin (FLG), in the skin of PPAR-γ-deficient mice (rev. in ^[18][124]). At the same time, they fail to produce similar changes in the skin of PPAR-β/δ- and RXR-α-deficient animals. Thus, these findings suggest that, unlike other PPARs, PPAR-γ can directly modulate the terminal differentiation of epidermal keratinocytes.

The agonists of PPAR-γ protect the skin from cutaneous inflammation. They suppress the genes of proinflammatory cytokines in resident skin cells. They also exhibit similar effects in invading immunocytes, vascular smooth muscle, and dendritic cells. The biological effect requires the activation of PPAR-γ, which, in turn, initiates the transrepression of NFκB and AP1 ^[19][20][125,126]. To be precise, the formation of inhibitory complexes between PPAR-γ and the named transcription factors suppress the genes of proinflammatory cytokines (IL6, IL8, IL12, IL21, IL23, and TNF). It also downregulates the expression of cyclooxygenase-2/COX-2/PTGS2 ^[21][127].

When discussing the ability of PPAR-γ to inhibit the expression of proinflammatory cytokines, reswearchers must acknowledge that complete blocking of the transcription factor NFκB by its specific inhibitors produces the opposite effect. Primarily, it significantly increases the proliferation of epidermal keratinocytes (rev. in ^[22][128]). Moreover, grafting the skin cells expressing a dominant-negative mutant IκBα on immunocompromised mice produces psoriasis-like skin lesions ^[23][129]. In addition, knocking out IKKα not only blocks NFκB, but also causes thickening of the epidermis. It also results in hyperplasia and impairs the terminal differentiation of epidermal keratinocytes ^[24][130]. In addition, treatment of the skin with UV light and dithranol induces NFκB and produces antipsoriatic effects in the epidermis ^[25][131]. RWesearchers presume that these findings suggest that transrepression does not block some forms of NFκB from binding to the DNA, whereas its complete disabling results in much harsher consequences. In addition to their effects on growth and differentiation, TZDs also suppress the motility of cultured epidermal keratinocytes of the basal layer during wound healing ^[9][115]. This biological effect has relevance for psoriasis because the disease causes a weakening of the intercellular contacts in the epidermis. In this regard, modulating the cell motility will interfere with spreading the immune cells across the skin.

The biological effects of PPAR-γ and its agonists are also evident in the other types of skin cells. The activator of PPAR-γ rosiglitazone impairs melanogenesis in melanocytes ^[26][132]. Another PPAR-γ agonist, ciglitazone, induces the apoptosis of melanocytes in a dose-dependent manner ^[27][133]. Contrarily, treatment of cultured melanocytes with GW9662, the antagonist of PPAR-γ, stimulates their differentiation ^[28][134]. In addition, PPAR-γ agonists may influence the motility of melanocytes. According to Denkins et al., dietary ω-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decreased the motility of cultured 70W cells. At the same time, ω-6 PUFAs such as arachidonic acid produced the opposite effect ^[29][135].

In the sebaceous glands, the expression of PPAR-γ significantly increases during puberty ^[30][136]. PPAR-γ is also abundantly expressed by skin adipocytes, playing a crucial role in their differentiation ^[31][137]. Overexpression of PPAR-γ in fibroblasts decreases their expression of adhesion molecules ICAM1 and VCAM1, preventing the recruitment of leukocytes to the endothelial cells ^[32][138]. In vascular endothelial cells stimulated with 13-PMA, the agonists of PPAR-γ (15d-PGJ(2), ciglitazone, and troglitazone) reduce the expression of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin ^[33][139]. In turn, the PPAR-γ agonist ciglitazone partially inhibits the production of chemokine C-C motif ligand 2 (CCL2) in the cells stimulated with C-reactive protein ^[34][140]. In addition, PPAR-γ modulates the INF-γ-induced expression of the chemokines CXCL9, -10, and -11, which subsequently reduces the chemotaxis of invading lymphocytes ^[35][141].

In summary, the level of PPAR-γ is low compared to other isotypes. In lesional skin, it is even less than in healthy skin. Among psoriasis patients, patients with multiple sclerosis express less PPAR-γ compared to the others. In mice and cultured cells, the agonists of PPAR-γ produce various biological effects that are potentially beneficial for psoriasis. They reduce the proliferation of epidermal keratinocytes and normalize their differentiation. They accelerate the restoration of the damaged skin barrier and suppress the genes of proinflammatory cytokines and adhesion molecules. In addition, they may potentially interfere with the infiltration of the skin by immune cells. Moreover, the agonists of PPAR-γ are efficient in other types of skin cells.

The migration of immune cells to lesional psoriatic skin causes their gradual accumulation in the plaques. It significantly changes the cellular composition of skin areas affected by the disease, altering the metabolism of resident skin cells and changing their appearance and functionality. In total, lesional skin may accumulate up to 20 million of the 28–30 million leukocytes in the human body ^[36][142]. In this regard, rwesearchers would like to discuss the role of PPAR-γ in infiltrated immune cells due to their intensive crosstalk with resident skin cells.

A typical psoriatic infiltrate contains at least four major types of immune cells—lymphocytes, macrophages, dendritic cells, and neutrophils. The cellular composition of psoriatic infiltrate is not the same at various stages of the disease ^[37][143]. The ratio of macrophages reaches the maximum at the time when the disease exacerbates and psoriatic plaques continue to grow. The fraction of CD8⁺ Tc cells decreases with time. In contrast, the fractions of CD4⁺ T cells such as Th₁, Th₁₇, and Th₂₂ increase even after the plaque growth slows down. The presence of neutrophils increases after the inflammatory process has already stabilized. The mentioned immune cells are preferably located in different parts of lesional skin because their mobility and the ability to interact with ECM are not the same ^[38][39][144,145]. CD4⁺ Th cells predominantly reside in the epidermis, whereas CD8⁺ T cells and neutrophils are in the dermis ^[40][146]. Macrophages accumulate in the dermal papillae and deeper dermis around the dilated superficial vessels. Moreover, they are also present in lymphohistiocytic infiltrates. In addition, large groups of immune cells remain in the papillary and reticular layers of the dermis ^[41][147].

Previous studies demonstrated that PPARs are highly expressed in macrophages ^[42][148], dendritic cells ^[43][149], neutrophils ^[44][150], B cells ^[45][151], and T cells ^[46][66]. In immune cells, PPAR-γ regulates their lipid metabolism and modulates the immune response. It influences their differentiation and proliferation. It controls the expression of cytokines and chemokines. Under certain conditions, the agonists of PPAR-γ induce the apoptosis of immune cells. The direct participation of PPAR-γ in various metabolic and signaling pathways makes it a potential molecular target for chronic inflammatory disorders such as psoriasis (rev. in ^[47][152]). In the following discussion, rwesearchers will focus on the role of PPAR-γ in mediating the specific immune functions that are characteristic of certain types of immune cells altered in psoriasis.