Metabolomic Differences between the Skin and Blood Sera of Atopic Dermatitis and Psoriasis.

Atopic dermatitis (AD) and psoriasis (PS) are common chronic inflammatory dermatoses. Although the differences at the intercellular and intracellular signaling level between AD and PS are well described, the resulting differences at the metabolism level have not yet been systematically analyzed. We compared the metabolomic profiles of the lesional skin, non-lesional skin and blood sera of AD and PS. Skin biopsies from 15 patients with AD, 20 patients with PS and 17 controls were collected, and 25 patients with AD, 55 patients with PS and 63 controls were recruited for the blood serum analysis. Serum and skin samples were analyzed using a targeted approach to find the concentrations of 188 metabolites and their ratios. A total of 19 metabolites differed in the comparison of lesional skins, one metabolite in non-lesional skins and 5 metabolites in blood sera. Although we found several metabolomic similarities between PS and AD, clear differences were outlined. Sphingomyelins were elevated in lesional skin of AD, implying a deficient barrier function. Increased levels of phosphatidylcholines, carnitines and asymmetric dimethylarginine in PS lesional skin and carnitines amino acids in the PS serum pointed to elevated cell proliferation. The comparison of the metabolomic profiles of AD and PS skin and sera outlined distinct patterns that were well correlated with the differences in the pathogenetic mechanisms of these two chronic inflammatory dermatoses.

Metabolomic Analysis of Skin Biopsies from Patients with Atopic Dermatitis Reveals Hallmarks of Inflammation, Disrupted Barrier Function and Oxidative Stress.

The main objectives of this study were to characterize the metabolomic profile of lesional skin of patients with atopic dermatitis, and to compare it with non- lesional skin of patients with atopic dermatitis and skin of controls with no dermatological disease. Skin-punch biopsies were collected from 15 patients and 17 controls. Targeted analysis of 188 metabolites was conducted. A total of 77 metabolites and their ratios were found, which differed significantly between lesional skin of atopic dermatitis, non-lesional skin of atopic dermatitis and skin of controls. The metabolites were members of the following classes: amino acids, biogenic amines, acylcarnitines, sphingomyelins or phosphatidylcholines, and the most significant differences be-tween the groups compared were in the concentrations of putrescine, SM.C26.0 and SM.C26.1. The alterations in metabolite levels indicate inflammation, impaired barrier function, and susceptibility to oxidative stress in atopic skin.

Hyperproliferation is the main driver of metabolomic changes in psoriasis lesional skin.

Systematic understanding of the metabolite signature of diseases may lead to a closer understanding of the disease pathogenesis and ultimately to the development of novel therapies and diagnostic tools. Here we compared for the first time the full metabolomic profiles of lesional and non-lesional skin biopsies obtained from plaque psoriasis patients and skin samples of healthy controls. Significant differences in the concentration levels of 29 metabolites were identified that provide several novel insights into the metabolic pathways of psoriatic lesions. The metabolomic profile of the lesional psoriatic skin is mainly characterized by hallmarks of increased cell proliferation. As no significant differences were identified between non-lesional skin and healthy controls we conclude that local inflammatory process that drives the increased cell proliferation is the main cause of the identified metabolomic shifts.

SERPINB2 and miR-146a/b are coordinately regulated and act in the suppression of psoriasis-associated inflammatory responses in keratinocytes.

Psoriasis is a chronic inflammatory skin disease with numerous involved factors. miR-146a and miR-146b (miR-146a/b) are anti-inflammatory miRNAs that are increased in psoriatic skin. SERPINB2 has been shown to be upregulated in the inflammation and infections. Here we aimed to study the relationship between miR-146a/b and SERPINB2 and to delineate the role of SERPINB2 in association of plaque psoriasis. We report increased SERPINB2 expression in the skin of psoriasis patients, which was in a positive relationship with psoriasis severity and in a negative relationship with miR-146a/b in psoriatic lesions. In cultured keratinocytes, both cellular and secreted SERPINB2 levels were strongly induced in response to IFN-γ and TNF-α. Interestingly, SERPINB2 mRNA was downregulated by IL-17A and the combination of TNF-α and IL-17A at time points when miR-146a was increased. The predicted binding site for miR-146a/b in 3' untranslated region of SERPINB2 revealed no activity in luciferase assay, while siRNA silencing of miR-146a/b direct targets IRAK1 and CARD10 resulted in reduced expression of SERPINB2, suggesting that miR-146a/b indirectly control SERPINB2 expression in the skin. The siRNA silencing of SERPINB2 increased the expression of IL-8, CXCL5 and CCL5 and migration of neutrophils revealing its anti-inflammatory role in keratinocytes. Our data together suggest that SERPINB2 and miR-146a/b are part of disease-related network of molecules that are coordinately regulated and act in controlling the inflammatory responses in psoriatic skin.

miR-10a-5p is increased in atopic dermatitis and has capacity to inhibit keratinocyte proliferation.

BACKGROUND: miR-10a-5p has been shown to regulate cancer cell proliferation and invasiveness and endothelial cell inflammatory responses. The function of miR-10a-5p in the skin has not been previously studied. The aim of the current study was to examine miR-10a-5p expression, regulation, and function in keratinocytes (KCs) in association with atopic dermatitis (AD). METHODS: The expression of miR-10a-5p and its target genes was analyzed using RT-qPCR, mRNA array analysis, in situ hybridization, and immunofluorescence. The transfection of miRNA mimics, cell cycle distribution analysis, and luciferase assays was used to study miR-10a-5p functions in human primary KCs. RESULTS: miR-10a-5p was found to be upregulated in lesional skin from patients with AD and in proliferating KCs. Array and pathway analysis of IL-1ß-stimulated KCs revealed that miR-10a-5p inhibited many genes that affect cell cycle progression and only a few inflammation-related genes. Accordingly, fewer cells in S-phase and reduced proliferation were detected as characteristics of miR-10a-5p-transfected KCs. The influence of miR-10a-5p on cell proliferation was also evident in KCs induced by AD-related cytokines, including IL-4, IL-17, and IL-1ß, as measured by the capacity to strongly suppress the expression of the proliferation marker Ki-67. Among AD-related putative direct target genes, we verified hyaluronan synthase 3, a damage-associated positive regulator of KC migration and proliferation, as a direct target of miR-10a-5p. CONCLUSIONS: miR-10a-5p inhibits KC proliferation and directly targets hyaluronan synthase 3 and thereby may modulate AD-associated processes in the skin.

miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis.

miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In this study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in the lesional skin of patients with psoriasis. The expression of miR-146a was approximately twofold higher than that of miR-146b in healthy human skin, and it was more strongly induced by stimulation of proinflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of patients with psoriasis, among which FERMT1 was verified as a direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in the miR-146a encoding gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a-/- and skin fibroblasts from miR-146a-/- and miR-146b-/- mice stimulated with psoriasis-associated cytokines as compared with wild-type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin.