Control Skin Research Articles

Peripheral Hybrid CB1R and iNOS Antagonist MRI-1867 Displays Anti-Fibrotic Efficacy in Bleomycin-Induced Skin Fibrosis.

Scleroderma, or systemic sclerosis, is a multi-organ connective tissue disease resulting in fibrosis of the skin, heart, and lungs with no effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) and increased activity of inducible NO synthase (iNOS) promote tissue fibrosis including skin fibrosis, and joint targeting of these pathways may improve therapeutic efficacy. Recently, we showed that in mouse models of liver, lung and kidney fibrosis, treatment with a peripherally restricted hybrid CB1R/iNOS inhibitor (MRI-1867) yields greater anti-fibrotic efficacy than inhibiting either target alone. Here, we evaluated the therapeutic efficacy of MRI-1867 in bleomycin-induced skin fibrosis. Skin fibrosis was induced in C57BL/6J (B6) and Mdr1a/b-Bcrp triple knock-out (KO) mice by daily subcutaneous injections of bleomycin (2 IU/100 µL) for 28 days. Starting on day 15, mice were treated for 2 weeks with daily oral gavage of vehicle or MRI-1867. Skin levels of MRI-1867 and endocannabinoids were measured by mass spectrometry to assess target exposure and engagement by MRI-1867. Fibrosis was characterized histologically by dermal thickening and biochemically by hydroxyproline content. We also evaluated the potential increase of drug-efflux associated ABC transporters by bleomycin in skin fibrosis, which could affect target exposure to test compounds, as reported in bleomycin-induced lung fibrosis. Bleomycin-induced skin fibrosis was comparable in B6 and Mdr1a/b-Bcrp KO mice. However, the skin level of MRI-1867, an MDR1 substrate, was dramatically lower in B6 mice (0.023 µM) than in Mdr1a/b-Bcrp KO mice (8.8 µM) due to a bleomycin-induced increase in efflux activity of MDR1 in fibrotic skin. Furthermore, the endocannabinoids anandamide and 2-arachidonylglycerol were elevated 2-4-fold in the fibrotic vs. control skin in both mouse strains. MRI-1867 treatment attenuated bleomycin-induced established skin fibrosis and the associated increase in endocannabinoids in Mdr1a/b-Bcrp KO mice but not in B6 mice. We conclude that combined inhibition of CB1R and iNOS is an effective anti-fibrotic strategy for scleroderma. As bleomycin induces an artifact in testing antifibrotic drug candidates that are substrates of drug-efflux transporters, using Mdr1a/b-Bcrp KO mice for preclinical testing of such compounds avoids this pitfall.

Financial burden and impact of atopic dermatitis out-of-pocket healthcare expenses among black individuals in the United States

Black race is associated with increased atopic dermatitis (AD) severity and healthcare resource utilization. However, the burden of out-of-pocket (OOP) expenses among black individuals with AD is not well understood. We sought to characterize the categories and impact of OOP healthcare expenses associated with AD management among black individuals. A 25-question voluntary online survey was administered to National Eczema Association members (N = 113,502). Inclusion criteria (US residents age ≥ 18 years; self-report of AD or primary caregivers of individuals with AD) was met by 77.3% (1118/1447) of respondents. Black individuals with AD were younger, had lower household income, Medicaid, urban residence, poor AD control and frequent skin infections (P ≤ 0.02). Blacks vs. non-blacks reported more OOP costs for prescription medications covered (74.2% vs. 63.6%, P = 0.04) and not covered (65.1% vs. 46.5%, P = 0.0004) by insurance, emergency room visits (22.1% vs. 11.8%, P = 0.005), and outpatient laboratory testing (33.3% vs. 21.8%, P = 0.01). Black race was associated with increased household financial impact from OOP expenses (P = 0.0009), and predictors of financial impact included minimally controlled AD (adjusted OR [95% CI] 13.88 [1.63–117.96], P = 0.02), systemic therapy (4.34 [1.63–11.54], 0.003), > $200 monthly OOP expenses (14.28 [3.42–59.60], P = 0.0003), and Medicaid (4.02 [1.15–14.07], P = 0.03). Blacks with Medicaid had higher odds of harmful financial impact (3.32 [1.77–6.24], P = 0.0002) than those of black race (1.81 [1.04–3.15], P = 0.04) or with Medicaid (1.39 [1.02–1.88], P = 0.04) alone. Black race is associated with increased OOP costs for AD and significant household financial impact. Targeted interventions are needed to address financial disparities in AD.

The Effect of Feeding Hens a Peanut Skin-Containing Diet on Hen Performance, and Shell Egg Quality and Lipid Chemistry

Peanut skins are a considerable waste product with little current economic value or use. We aimed to determine the dietary effects of peanut skins on layer production performance and egg quality and chemistry of the eggs produced. Two hundred commercial hens were randomly assigned to four treatments (five replicates) and fed ad libitum for 8 weeks: conventional control diet, diet containing 24% high-oleic peanut (HOPN), diet containing 3% peanut skin (PN Skin), and a diet with 2.5% oleic acid (OA). Hens fed the HOPN diet had significantly reduced body weights relative to the control and PN Skin treatments, producing fewer total eggs over the 8-week experimental period. Eggs weights were similar between the control and PN Skin treatments at weeks 2 and 4, while eggs from the PN Skin treatment group were heavier than other treatments at weeks 6 and 8 of the experiment. Eggs produced from the HOPN treatment had reduced saturated fatty acid (FA) content in comparison to the other treatment groups, while similar between PN Skin and control eggs at week 8 of the experiment. This study suggests that PN skins may be a suitable alternative layer feed ingredient.

Aryl hydrocarbon receptor controls skin homeostasis, regeneration, and hair follicle cycling by adjusting epidermal stem cell function.

Skin integrity requires constant maintenance of a quiescent, yet responsive, population of stem cells. While interfollicular epidermal progenitors control normal homeostasis, hair follicle stem cells residing within the bulge provide regenerative potential during hair cycle and in response to wounding. The aryl hydrocarbon receptor (AhR) modulates cell plasticity and differentiation and its overactivation results in severe skin lesions in humans. However, its physiological role in skin homeostasis and hair growth is unknown. Reconstitution assays grafting primary keratinocytes and dermal fibroblasts into nude mice and 3-D epidermal equivalents revealed a positive role for AhR in skin regeneration, epidermal differentiation, and stem cell maintenance. Furthermore, lack of receptor expression in AhR-/- mice delayed morphogenesis and impaired hair regrowth with a phenotype closely correlating with a reduction in suprabasal bulge stem cells (α6low CD34+ ). Moreover, RNA-microarray and RT-qPCR analyses of fluorescence-activated cell sorting (FACS)-isolated bulge stem cells revealed that AhR depletion impaired transcriptional signatures typical of both epidermal progenitors and bulge stem cells but upregulated differentiation markers likely compromising their undifferentiated phenotype. Altogether, our findings support that AhR controls skin regeneration and homeostasis by ensuring epidermal stem cell identity and highlights this receptor as potential target for the treatment of cutaneous pathologies.

Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide (Niacinamide) to Control Skin Aging and Pigmentation.

Vitamin B3 (nicotinic acid, niacin) deficiency causes the systemic disease pellagra, which leads to dermatitis, diarrhea, dementia, and possibly death depending on its severity and duration. Vitamin B3 is used in the synthesis of the NAD+ family of coenzymes, contributing to cellular energy metabolism and defense systems. Although nicotinamide (niacinamide) is primarily used as a nutritional supplement for vitamin B3, its pharmaceutical and cosmeceutical uses have been extensively explored. In this review, we discuss the biological activities and cosmeceutical properties of nicotinamide in consideration of its metabolic pathways. Supplementation of nicotinamide restores cellular NAD+ pool and mitochondrial energetics, attenuates oxidative stress and inflammatory response, enhances extracellular matrix and skin barrier, and inhibits the pigmentation process in the skin. Topical treatment of nicotinamide, alone or in combination with other active ingredients, reduces the progression of skin aging and hyperpigmentation in clinical trials. Topically applied nicotinamide is well tolerated by the skin. Currently, there is no convincing evidence that nicotinamide has specific molecular targets for controlling skin aging and pigmentation. This substance is presumed to contribute to maintaining skin homeostasis by regulating the redox status of cells along with various metabolites produced from it. Thus, it is suggested that nicotinamide will be useful as a cosmeceutical ingredient to attenuate skin aging and hyperpigmentation, especially in the elderly or patients with reduced NAD+ pool in the skin due to internal or external stressors.

The inflammatory proteome of hidradenitis suppurativa skin is more expansive than that of psoriasis vulgaris

Although hidradenitis suppurativa (HS) shares some transcriptomic and cellular infiltrate features with psoriasis, their skin proteome remains unknown. To define and compare inflammatory protein biomarkers of HS and psoriasis skin. We assessed 92 inflammatory biomarkers in HS (n=13), psoriasis (n=11), and control skin (n=11) using Olink high-throughput proteomics. We also correlated HS skin and blood biomarkers using proteomics and RNA sequencing. We identified 57 differentially expressed proteins (DEPs) in lesional psoriasis and 64 DEPs in lesional HS skin, compared to healthy controls. Both HS and psoriasis lesional skin demonstrated a significant upregulation of T helper 1 and T helper 17 proteins. Healthy-appearing perilesional HS skin had 63 DEPs compared to healthy controls. Nonlesional HS and psoriasis skin had 24 and 7 DEPs, respectively, compared to healthy controls. Tumor necrosis factor and 8 other proteins were significantly correlated with clinical severity in perilesional HS skin (2cm from a nodule). Inclusion of only moderate-to-severe patients and the cohort size. HS has a greater inflammatory profile and is more diffusely distributed compared with psoriasis. Proteins correlated with disease severity are potential disease mediators. Perilesional skin is comparably inflamed to lesional skin, suggesting the need to treat beyond skin nodules.

Characterization of mononeuropathy of the lateral cutaneous nerve of the calf.

Isolated injuries to the lateral cutaneous nerve of the calf (LCNC) branch of the common peroneal nerve can cause obscure chronic posterolateral knee and upper calf pain and sensory symptoms. Routine examination and electrodiagnostic testing do not detect them because the LCNC has no motor distribution and it is not interrogated by the typical peroneal nerve conduction study. There are only about 10 prior cases, thus scant physician awareness, so most LCNC injuries remain misdiagnosed or undiagnosed, hindering care. We extracted pertinent records from seven patients with unexplained posterolateral knee/calf pain, six labeled as complex regional pain syndrome, to investigate for mononeuropathies. Patients were asked to outline their skin area with abnormal responses to pin self-examination independently. Three underwent an LCNC-specific electrodiagnostic study, and two had skin-biopsy epidermal innervation measured. Cadaver dissection of the posterior knee nerves helped identify potential entrapment sites. Initiating events included knee surgery (three), bracing (one), extensive kneeling (one), and other knee trauma. All pin-outlines included the published LCNC neurotome. One oftwo LCNC-specific electrodiagnostic studies revealed unilaterally absent potentials. Longitudinal, controlled skin biopsies documented profound LCNC-neurotome denervation then re-innervation contemporaneous with symptom recovery. Cadaver dissection identified the LCNC traversing through the dense fascia of the proximolateral gastrocnemius muscle insertion. Isolated LCNC mononeuropathy can cause unexplained posterolateral knee/calf pain syndromes. This series characterizes presentations and supports patient pin-mappings as a sensitive, globally available, low-cost diagnostic aid. Improved recognition may facilitate more rapid, accurate diagnosis and, thus, optimize management and improve outcomes.

Vesicular hand eczema transcriptome analysis provides insights into its pathophysiology.

Hand eczema is a common inflammatory skin condition of the hands whose pathogenesis is largely unknown. More insight and knowledge of the disease on a more fundamental level might lead to a better understanding of the biological processes involved, which could provide possible new treatment strategies. We aimed to profile the transcriptome of lesional palmar epidermal skin of patients suffering from vesicular hand eczema using RNA‐sequencing. RNA‐sequencing was performed to identify differentially expressed genes in lesional vs. non‐lesional palmar epidermal skin from a group of patients with vesicular hand eczema compared to healthy controls. Comprehensive real‐time quantitative PCR analyses and immunohistochemistry were used for validation of candidate genes and protein profiles for vesicular hand eczema. Overall, a significant and high expression of genes/proteins involved in keratinocyte host defense and inflammation was found in lesional skin. Furthermore, we detected several molecules, both up or downregulated in lesional skin, which are involved in epidermal differentiation. Immune signalling genes were found to be upregulated in lesional skin, albeit with relatively low expression levels. Non‐lesional patient skin showed no significant differences compared to healthy control skin. Lesional vesicular hand eczema skin shows a distinct expression profile compared to non‐lesional skin and healthy control skin. Notably, the overall results indicate a large overlap between vesicular hand eczema and earlier reported atopic dermatitis lesional transcriptome profiles, which suggests that treatments for atopic dermatitis could also be effective in (vesicular) hand eczema.

Design, Synthesis, In silico and In Vitro Anticancer Activity of Novel Bis‐Furanyl‐Chalcone Derivatives Linked through Alkyl Spacers

AbstractA novel series of bis(furan‐based chalcone) derivatives linked to aliphatic linkers, with the furan units at the A‐ or B‐rings, were synthesized and evaluated as anticancer agents. Chalcones 5 a–c in which the furan ring designed to be a B‐ring were obtained from the Knoevenagel condensation reactions of the appropriate bis(acetyl) compounds 3 a–c with two equivalents of furan‐2‐aldehyde. Likewise, the condensation of bis(aldehydes) 7 a–c with two equivalents of 2‐acetylfuran afforded the corresponding chalcones 9 a–c, in which the furan rings represent the A‐rings of the chalcones, in excellent yields. The synthesized compounds have been fully characterized by 1H‐NMR, 13C‐NMR, and elemental analysis. The in vitro anticancer activity of the prepared compounds was tested against A549, HCT116, HePG2, PC3, A431 and BJ1 cell lines using MTT assay, gene expression analysis of skin and lung cancer related genes, comet assay, and DNA fragmentation assy. Compounds 9 a and 9 c were found to be the most promising, with IC50 (24.9 and 13.7 μg/ml, respectively) against A549 compared with doxorubicin (IC50, 28.3 μg/ml) and IC50 (26.1 and 14.4 μg/ml, respectively) against A431 in comparison to doxorubicin (IC50, 24.9 μg/ml). Comapred with neagtive control cell lines, the gene expression levels of hBD‐2 and hBD‐3 genes were decreased singnificantly (P<0.05) in positive control and skin cancer cell lines (A431) treated with compounds 9 a and 9 c. The expression levels of FOSB and IL‐8 genes were increased singnificantly (P<0.05) in positive control and lung cancer cell lines (A549 and A541) treated with compounds 9 a and 9 c, respectively, comapred with neagtive control cell lines. The DNA damage was increased significantly (P<0.001) in treated skin and lung cell lines samples compared with negative control. The negative control skin and lung cancer cell lines showed a significant decrease (P< 0.05) in DNA fragmentation rate compared with positive control. On the other hand, the DNA fragmentation rates were increased significantly (P<0.001) in treated skin and lung cell lines samples compared with negative control. In summary, the synthesized compounds 9 a and 9 c showed a significant anticancer activity against lung and skin cancer cell lines compared with known chemotherapeutic drug (doxorubicin).

Gene Expression Profiling in the Skin Reveals Strong Similarities between Subacute and Chronic Cutaneous Lupus that Are Distinct from Lupus Nephritis

Subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are represented in the majority of cutaneous lupus subtypes, each of which has variable implications for systemic manifestations such as lupus nephritis. On dermatologic examination, subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are distinct. However, it is often difficult to diagnose the subtype from histology alone. Our study utilized whole-genome microarray expression analysis on human skin samples of subacute cutaneous lupus erythematosus, on human skin samples of chronic cutaneous lupus erythematosus, and on healthy controls, along with analysis on human samples of lupus nephritis and normal kidney tissue to compare cutaneous lupus subtypes with each other as well as with lupus nephritis. The data revealed that cutaneous lupus subtypes were distinct from healthy control skin, with gene expression predominantly characterized by upregulation of IFN-1 and T-cell chemotactic genes. However, the cutaneous lupus subtypes were very similar to one another; comparative analyses revealed few statistically significant differences in gene expression. There were also distinct differences between the gene signatures of cutaneous lupus and lupus nephritis. Cutaneous lupus samples revealed gene signatures demonstrating a prominent inflammatory component that may suggest the skin as an early site of initiation of lupus pathogenesis, whereas lupus nephritis reflected the recruitment and activation of M2 macrophages and a wound healing signature.

Evaluation of the clinical effectiveness of the method of Skin Rejuvenation using Electrostimulation

Objectives: Purpose of the study evaluation of the cosmetic effect using the "Ajayan" plaster for facial rejuvenation. Materials and Methods: The study was carried out in 106 participants with presence of perioral wrinkles of the skin. Participants applied four patches (2 copper and 2 zinc) on the face in the area of wrinkles crosswise according to the instructions. The patches were applied for eight hours every third day for three months. The participants tactilely and visually assessed the effects of the patch for three months. Clinical assessment of treatment results (satisfaction by subject and investigator physician) was performed. The immediate results were assessed 1 month after the course and long-term results at the end of 3 months of observation. Perioral wrinkles were assessed by comparing photographs at the beginning and at the end of the study for each individual case. The efficacy was assessed according to the International Global Aesthetic Improvement Scale (GAIS Table 1-3) on the 1st (M01), 2nd (M02), 3rd (M03), 6th (M06) month of complex therapy. Visual confirmation of clinical improvement was also obtained by Life Viz 3D camera pictures. Results: After analyzing the photographs taken before and after using the patch (Figure 1-3) and a personal conversation with each participant, the following data were obtained from participants: • a decrease in puffiness and dark circles under the eyes was noted: 6 out of 15 men, 34 out of 91 women; • smoothing of small mimic wrinkles was noted: 24 women out of 106 people; • lifting of the face oval was noted: 14 women out of 106 people. Evaluation of the effectiveness of the GAIS procedure on M03 and M05, 2/3 of patients had significant improvement as assessed by physician and participants according to GAIS (Table 3). Most of the patients also showed significant improvement at visit M12, Table 3. After analyzing the photographs taken before and after the experiment, and a personal conversation with each patient of the cosmetology profile, the following results were obtained: in 38% of patients, puffiness and dark circles under the eyes decreased, in 23% of participants fine facial wrinkles were smoothed, in 12% of participants the oval of the face was tightened. Our results suggest that "Ajanyan" plaster can serve as a novel therapy for controlled skin rejuvenation, effective wrinkles and folds. Conclusion: The results of the studies provide a basis for concluding that the method of skin rejuvenation using electrostimulation method is effective on the clinical manifestations skin. The "Ajayan" plaster has proven its effectiveness through electrical stimulation with low intensity current in patients in different age groups, the study revealed a large number of positive cosmetic effects. Keywords: Wrinkles; Skin rejuvenation; Novel method of electrostimulation

High inflammation in hidradenitis suppurativa extends to perilesional skin and can be subdivided by lipocalin-2 expression

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with diverse manifestations ranging from nodules and abscesses to draining tunnels. Whether the underlying inflammation from lesions extends to relatively healthy-appearing adjacent perilesional and distant nonlesional skin has not been systematically evaluated. We sought to characterize lesional, perilesional, and nonlesional skin in patients with HS. Skin biopsy samples were collected under ultrasound guidance from patients with active, untreated moderate-to-severe HS. Site-matched control biopsy samples from healthy volunteers were used for comparison. RNA sequencing demonstrated that HS skin clustered separately from healthy control skin, with perilesional and lesion skin clustering together and away from nonlesional skin. Immunohistochemistry analysis identified psoriasiform hyperplasia with keratin 16 positivity in both perilesional and lesional skin, with comparable levels of CD3+, CD11c+, and neutrophil elastase-positive cellular infiltration. There was a marked upregulation of IL-17 signaling in perilesional and lesional skin. HS samples clustered on the basis of expression of lipocalin-2 (LCN2), with samples characterized by high LCN2 expression in the skin exhibiting a differing transcriptomic profile with significantly higher overall inflammation than that of skin characterized by low LCN2 levels. Perilesional HS skin has a transcriptomic and molecular profile comparable to that of lesional skin. HS can be grouped into 2 distinct subtypes based on molecular levels of LCN2 in the skin, with the LCN2-high subtype exhibiting an overall higher inflammatory burden and an upregulation of targetable cytokines. To our knowledge, this is the first study to characterize a unique HS subtype (and a potential endotype) that may guide future therapeutic targets.

The role of LncRNA MALAT-1 and MiRNA-9 in Psoriasis

BackgroundPsoriasis is a chronic skin disorder manifested by recurrent episodes of scaly, red, itchy skin patches that occur within apparently normal skin. ObjectivesThis study was performed to detect the expression of serum and tissue (lesion and non-lesion) LncRNA MALAT-1 and MiRNA-9 that might be used as biomarkers for psoriasis. MethodsBlood samples were obtained from 60 psoriasis patients and 40 controls, as well as 4 mm punch biopsy from lesional and non lesional skin of psoriatic patient and normal skin of healthy controls. Expression of LncRNA MALAT-1 and miRNNA-9 in serum and tissues was detected by real time qRT-PCR. Resultsa statistically significant increase in the expression of MALAT-1 in lesional and non-lesional skin and serum of psoriatic patients in comparison to controls were detected. Moreover, there was statistically significant increase in serum MiRNA-9 in patients in comparison to controls, while its tissue level was significantly lower in patients. ConclusionThis study highlights the dysregulation of LncRNA MALAT-1 and miRNA-9 in psoriasis. Elevated expression of MALAT-1 in lesional skin of psoriatic patients compared to non-lesional skin may possibly contribute to the development of psoriatic plaques.

Homozygous ITGA3 Missense Mutation in Adults in a Family with Syndromic Epidermolysis Bullosa (ILNEB) without Pulmonary Involvement

Homozygous ITGA3 Missense Mutation in Adults in a Family with Syndromic Epidermolysis Bullosa (ILNEB) without Pulmonary Involvement

Expression pattern of tissue-resident memory T cells in cutaneous lupus erythematosus.

Tissue resident memory T cells (TRMs) persist long-term in peripheral tissues without recirculation, triggering an immediate protective inflammatory state upon the re-recognition of the antigen. Despite evidence incriminating the dysregulation of TRMs in autoimmune diseases, few studies have examined their expression in cutaneous lupus erythematosus (CLE). We aimed to examine whether there are differences among TRM populations in CLE depending on different clinical conditions, such as the CLE subtype or association with systemic lupus erythematosus, and to determine the effect of type I interferon (IFN) on the development of TRMs in CLE. CLE disease activity was evaluated using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. The expression of the TRM markers CD69 and CD103 in CLE lesions was evaluated by immunofluorescence. Flow cytometry was performed on peripheral blood mononuclear cells after IFNα treatment. The number of TRMs expressing either CD69 or CD103 was significantly higher in CLE lesions than in control skin; however, it was not significantly different between discoid lupus erythematosus and subacute CLE, or dependent on the presence of concomitant systemic lupus. Lesional severity was not correlated with an increase in TRMs in CLE. IFNα treatment induced a conspicuous increase in CD69 expression in skin-homing T cells, more profoundly in CD4+ T cells than in CD8+ T cells. Skin TRMs, either CD69 or CD103-positive cells, showed increased levels in the lesional skin of CLE, and IFNα increased the expression of CD69 in T cells.

Comparison of Cytokines in Skin Biopsies and Tape Strips from Adults with Atopic Dermatitis

Skin biomarkers for disease severity and treatment response in atopic dermatitis (AD) are needed. Biopsies cause scarring and tape stripping represents an alternative minimally invasive method for stratum corneum sampling. In this study, we examined the gene expression of cytokines in skin biopsies and cytokines in stratum corneum tape strips collected from adults with AD. We collected punch biopsies and tape strips from healthy controls (n = 6) and subjects with AD (n = 12) at baseline and after 2 weeks of topical treatment with mometasone furoate 0.1% cream. We found that IFN-γ, IL-13, and IL-10 mRNA (biopsies) and IL-1β protein expression levels (tape strips) were significantly increased in lesional AD skin compared to healthy control skin. Treatment with topical corticosteroid led to a significant decrease in mRNA levels for IL-13 and IL-4R but no significant differences in cytokine protein levels measured in tape strips. Finally, we found no significant correlations between cytokine levels in tape strips and mRNA levels in skin biopsies.

Production of IL-31 in CD45RO+CLA+H4R+ T Cells in Atopic Dermatitis.

IL-31 is involved in pruritus in atopic dermatitis (AD) and the pathogenesis of AD. However, the mechanism of IL-31 production is not fully understood. We sought to investigate the association between CD45RO+CLA+H4R+ T cells and IL-31 production. Immunofluorescence studies were performed retrospectively on punch-biopsy specimens from five people with AD and three healthy controls. In addition, blood samples were collected prospectively from eight patients with AD and eight healthy controls for sorting CD45RO+CLA+H4R+ T cells. There was no overlap of patients between the biopsy group and the blood sampling group. Sorted cells were stimulated with 4-methylhistamine (4MH), and the level of IL-31 was measured by an enzyme-linked immunosorbent assay. Immunofluorescence showed co-localization of H4R and IL-31 in lesional AD skin but not in normal skin of healthy controls. The proportion of CLA+H4R+ T cells among CD3+CD45RO+ lymphocytes was 18.3 ± 6.2% in patients with AD and 11.2 ± 7.6% in healthy controls. In the AD group, production of IL-31 by CD45RO+CLA+H4R+ T cells increased from 32.4 ± 13.3 pg/mL to 47.5 ± 18.7 pg/mL by 4MH stimulation after 24 h (p < 0.001). However, in the control group, production of IL-31 was 20.1 ± 10.6 pg/mL without and 22.1 ± 9.3 pg/mL with 4MH stimulation (p > 0.05). According to our study, CD45RO+CLA+H4R+ T cells are an important source of IL-31 in AD, and may be a target for treatment of IL-31-induced pruritus.

Expression of epidermal antimicrobial peptides is increased in tinea pedis.

Tinea pedis is often chronic or recurrent, but not all individuals are equally susceptible to this infection. Dermatophytes are able to induce the expression of antimicrobial peptides and proteins (AMPs) in human keratinocytes and certain AMPs can inhibit the growth of dermatophytes. The focus of this study was to analyse the secretion of relevant AMPs, especially RNase 7, human beta-defensin-2 (hBD-2) and the S-100 protein psoriasin (S100A7), in patients with confirmed tinea pedis. To verify the diagnosis, skin scales were obtained from all patients (n=13) and the dermatophytes were identified by potassium hydroxide mount, culture and molecular analysis. To determine the AMP concentrations, the lesional skin area of the foot was rinsed with a buffer that was subsequently analysed by ELISA. The corresponding area of the other unaffected foot as well as defined healthy skin areas of the forearm and forehead and samples from age and gender-matched healthy volunteers served as controls. In tinea pedis patients the AMP concentrations were higher in lesional skin than in non-lesional skin and in healthy skin of controls. In particular, concentrations of hBD-2 and psoriasin were significantly elevated. The induction of AMPs in tinea pedis might be triggered directly by the dermatophytes; furthermore, attendant inflammation and/or differentiation processes may play a role. Our results indicate that there is no defect in the constitutive expression and induction of the analysed AMPs by dermatophytes in the epidermis of affected patients. However, it is not known why the elevated AMP concentrations fail to efficiently combat dermatophyte growth.

Single-cell transcriptomics applied to emigrating cells from psoriasis elucidate pathogenic versus regulatory immune cell subsets

In previous human skin single-cell data, inflammatory cells constituted only a small fraction of the overall cell population, such that functional subsets were difficult to ascertain. Our aims were to overcome the aforesaid limitation by applying single-cell transcriptomics to emigrating cells from skin and elucidate exvivo gene expression profiles of pathogenic versus regulatory immune cell subsets in the skin of individuals with psoriasis. We harvested emigrating cells from human psoriasis skin after incubation in culture medium without enzyme digestion or cell sorting and analyzed cells with single-cell RNA sequencing and flow cytometry simultaneously. Unsupervised clustering of harvested cells from psoriasis skin and control skin identified natural killer cells, T-cell subsets, dendritic cell subsets, melanocytes, and keratinocytes in different layers. Comparison between psoriasis cells and control cells within each cluster revealed that (1) cutaneous type 17 T cells display highly differing transcriptome profiles depending on IL-17A versus IL-17F expression and IFN-γ versus IL-10 expression; (2) semimature dendritic cells are regulatory dendritic cells with high IL-10 expression, but a subset of semimature dendritic cells expresses IL-23A and IL-36G in psoriasis; and (3) CCL27-CCR10 interaction is potentially impaired in psoriasis because of decreased CCL27 expression in basal keratinocytes. We propose that single-cell transcriptomics applied to emigrating cells from human skin provides an innovative study platform to compare gene expression profiles of heterogenous immune cells in various inflammatory skin diseases.

Expression of Transient Receptor Potential Channel of Melastatin number 8 (TRPM8) in Non- Melanoma Skin Cancer: A Clinical and Immunohistochemical study

ABSTRACT Transient Receptor Potential Channel of Melastatin number 8 (TRPM8) is abnormally expressed in many cancers as lung, however little is known about TRPM8 expression in non-melanoma skin cancer (NMSC) including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). This work aimed to study TRPM8 expression in NMSC. It included 100 skin biopsies (50 normal skin as control group, 15 BCC and 35 SCC). Immunohistochemical staining for TRPM8 was done and results were correlated with clinicopathological characters. There was significant higher TRPM8 H-score in NMSC than control skin. On comparing SCC cases to control, there was significant positive TRPM8 expression, strong intensity, diffuse pattern, cytoplasmic and nucleo-cytoplasmic localization and higher range of H-score in SCC. In contrast, BCC showed significant lower TRPM8 positive expression when compared to control skin. Higher TRPM8 H-score in SCC showed significant positive correlation with large tumor size and poor tumor differentiation.TRPM8 may be implicated in pathogenesis of NMSC. Its association with bad prognostic characters; potentiates its role as prognostic biomarker and open new chances for therapeutic intervention in NMSC. TRPM8 antagonists may share in decreasing tumor growth and progression and may serve as potential target for tumor immunotherapy.