Decreased retinoid concentration and retinoid signalling pathways in human atopic dermatitis

Abstract

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.

Reduced Retinoid Signaling in the Skin after Systemic Retinoid-X Receptor Ligand Treatment in Mice with Potential Relevance for Skin Disorders

“…In general, retinoid dysregulation in affected as well as nonaffected AD skin is one main feature of this disease [9]. In our study, thromboxane synthase and thromboxane receptor as well as 5-lipoxygenase and leukotriene B4 receptor [19,20] increased after oral RXR ligand treatment, which concludes that itch and scratch responses, partly responsible for the AD phenotype, are also co-initiated via increased systemic RXR-mediated signaling [37].…”

“…Dysregulation of retinoid metabolism is either the cause or the initiator of various diseases including allergic diseases [23,24]. Reduced concentrations of ATRA and retinol as well as reduced retinoid signaling are present in affected as well as nonaffected skin of AD patients [9]. In our studies, we observed that systemic treatment of a synthetic RXR ligand leads to reduced retinoid signaling in mouse skin and therefore it might possibly be relevant for reduced retinoid concentrations and retinoid signaling in mouse skin.…”

“…In a previous study, we observed strongly reduced reti-noid signaling and retinoid concentrations in affected as well as nonaffected skin of AD patients as compared to healthy individuals [9]. It is possible that this reduced retinoid signaling in the skin might be a key step for the development and/or chronification of AD.…”

Non-Pro-Vitamin A and Pro-Vitamin A Carotenoids in Atopy Development

“…It has been found that retinoid signaling, along with the expression of the various target genes involved, is generally much lower in the skin of patients with chronic atopic dermatitis than in that of healthy volunteers (table 2) [73]. Of note is the low expression of retinaldehyde dehydrogenase 1 (RALDH1), the enzyme mainly responsible for ATRA synthesis.…”

“…Numerous features like epidermal permeability [60], epidermal hyperproliferation [61], epidermal differentiation [54,62,63,64], sebum secretion [65], Th1/Th2 balance [52,66,67,68], apoptosis [69], lymphocyte proliferation [70], eosinophilia [71], chemokine secretion [53,72], inflammatory responses [52,67], retinoid signaling [73], thymic stromal lymphopoietin (TSLP) production [53] and bacterial colonization [74] are regulated by RAR and RXR pathways and are also severely dysregulated in atopic dermatitis (table 1). …”