Transient receptor potential (TRP) ion channels were first characterized on neurons, where they are classically implicated in sensory functions; however, research in recent decades has shown that many of these channels are also expressed on nonneuronal cell types. Emerging findings have highlighted the role of TRP channels in the skin, where they have been shown to be important in numerous cutaneous functions. Of particular interest is TRPV3, which was first described on keratinocytes. Its functional importance was supported when its gain-of-function mutation was linked to Olmsted syndrome, which is characterized by palmoplantar keratoderma, periorifacial hyperkeratosis, diffuse hypotrichosis and alopecia, and itch. Despite these exciting results, we have no information about the role and functionality of TRPV3 on keratinocytes at the cellular level. In this study, we identified TRPV3 expression both on human skin and cultured epidermal keratinocytes. TRPV3 stimulation was found to function as a Ca-permeable ion channel that suppresses proliferation of epidermal keratinocytes and induces cell death. Stimulation of the channel also triggers a strong proinflammatory response via the NF-κB pathway. Collectively, our data show that TRPV3 is functionally expressed on human epidermal keratinocytes and that it plays a role in cutaneous inflammatory processes.

Endogenous retinoids like all-trans retinoic acid (ATRA) play important roles in skin homeostasis and skin-based immune responses. Moreover, retinoid signaling was found to be dysregulated in various skin diseases. The present study used topical application of selective agonists and antagonists for retinoic acid receptors (RARs) α and γ and retinoid-X receptors (RXRs) for two weeks on mouse skin in order to determine the role of retinoid receptor subtypes in the gene regulation in skin. We observed pronounced epidermal hyperproliferation upon application of ATRA and synthetic agonists for RARγ and RXR. ATRA and the RARγ agonist further increased retinoid target gene expression (Rbp1, Crabp2, Krt4, Cyp26a1, Cyp26b1) and the chemokines Ccl17 and Ccl22. In contrast, a RARα agonist strongly decreased the expression of ATRA-synthesis enzymes, of retinoid target genes, markers of skin homeostasis, and various cytokines in the skin, thereby markedly resembling the expression profile induced by RXR and RAR antagonists. Our results indicate that RARα and RARγ subtypes possess different roles in the skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in skin. We suggest that dysregulated retinoid signaling in the skin mediated by RXR, RARα and/or RARγ may promote skin-based inflammation and dysregulation of skin barrier properties.

Lipoxygenases (LOX) and cyclooxygenase (COX) are the main enzymes for PUFA metabolism to highly bio‐active prostaglandins, leukotrienes, thromboxanes, lipoxins, resolvins and protectins. LOX and COX pathways are important for the regulation of pro‐inflammatory or pro‐resolving metabolite synthesis and metabolism for various inflammatory diseases such as atopic dermatitis (AD). In this study, we determined PUFAs and PUFA metabolites in serum as well as affected and non‐affected skin samples from AD patients and the dermal expression of various enzymes, binding proteins and receptors involved in these LOX and COX pathways. Decreased EPA and DHA levels in serum and reduced EPA level in affected and non‐affected skin were found; in addition, n3/n6‐PUFA ratios were lower in affected and non‐affected skin and serum. Mono‐hydroxylated PUFA metabolites of AA, EPA, DHA and the sum of AA, EPA and DHA metabolites were increased in affected and non‐affected skin. COX1 and ALOX12B expression, COX and 12/15‐LOX metabolites as well as various lipids, which are known to induce itch (12‐HETE, LTB4, TXB2, PGE2 and PGF2) and the ratio of pro‐inflammatory vs pro‐resolving lipid mediators in non‐affected and affected skin as well as in the serum of AD patients were increased, while n3/n6‐PUFAs and metabolite ratios were lower in non‐affected and affected AD skin. Expression of COX1 and COX‐metabolites was even higher in non‐affected AD skin. To conclude, 12/15‐LOX and COX pathways were mainly upregulated, while n3/n6‐PUFA and metabolite ratios were lower in AD patients skin. All these parameters are a hallmark of a pro‐inflammatory and non‐resolving environment in affected and partly in non‐affected skin of AD patients.

Atopic dermatitis (AD) is one of the most common skin diseases. Various features present in AD like inflammation, reduced apoptosis, altered epidermal differentiation and hyperproliferation as well as permeability dysfunction are also regulated by retinoids. The aim of our study is to identify the retinoid signalling pathways and retinoid concentration profiles in AD skin. Human skin biopsies were obtained from healthy volunteers (HS) (n = 6) and patients with AD (n = 6), with both affected (AS) and non-affected (NAS) skin. The gene expression of retinoid receptors, retinoid-binding proteins and retinoidmetabolizing enzymes was investigated by QRT-PCR. Retinoid concentrations in serum and skin were measured via high performance liquid chromatography mass spectrometry-mass spectrometry. Our results show that the target gene expression of retinoid receptor regulated pathways is significantly decreased in AS and NAS of patients with AD. CYP26A1, transglutaminase 2 and retinoic acid receptor responder 1 decreased in NAS and AS in comparison with HS. The main retinoic acid synthesizing enzyme, retinal dehydrogenase 1, was significantly lower expressed in NAS (0.1%) and AS (1%) in patients with AD. Analysis of retinoid concentration in serum and skin showed comparable all-trans retinoic acid (ATRA) and retinol (ROL) concentrations from AD and healthy serum, but strongly reduced ATRA and ROL concentrations in affected and non-affected skin in comparison with healthy skin. Our data indicate that retinoid transport, synthesis, concentrations and signalling are strongly decreased in the affected but also in non-affected skin of patients with AD suggesting a general intrinsic influence on skin retinoid signalling pathway in patients with AD.

Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high–vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal–vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high–vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand–induced, WAT-selective, increased retinoic acid response element–mediated signaling; and 3) RAR ligand–dependent reduction of adiponectin expression.—Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.