STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes.

Skin barrier dysfunction induces skin inflammation. Signal transducer and activator of transcription 3 (STAT3) is known to be involved in Th17-mediated immune responses and barrier integrity in the cornea and intestine; however, its role in the skin barrier remains largely unknown. In this study, we elucidated the potential role of STAT3 in the skin barrier and its effect on kallikrein-related peptidase 5 (KLK5) and serine protease inhibitor Kazal-type 5 (SPINK5) expression using a mouse model with keratinocyte-specific ablation of STAT3. Keratinocyte-specific loss of STAT3 induced a cutaneous inflammatory phenotype with pruritus and intense scratching behaviour in mice. Transcriptomic analysis revealed that the genes associated with impaired skin barrier function, including KLK5, were upregulated. The effect of STAT3 on KLK5 expression in keratinocytes was not only substantiated by the increase in KLK5 expression following treatment with STAT3 siRNA but also by its decreased expression following STAT3 overexpression. Overexpression and IL-17A-mediated stimulation of STAT3 increased the expression of SPINK5, which was blocked by STAT3 siRNA. These results suggest that the expression of SPINK5 and KLK5 in keratinocytes could be dependent on STAT3 and that STAT3 might play an essential role in the maintenance of skin barrier homeostasis.

Increased CD69+CCR7+ circulating activated T cells and STAT3 expression in cutaneous lupus erythematosus patients recalcitrant to antimalarials.

BACKGROUND: Antimalarials are first-line systemic therapy for cutaneous lupus erythematosus (CLE). While some patients unresponsive to hydroxychloroquine (HCQ) alone benefit from the addition of quinacrine (QC), a subset of patients is refractory to both antimalarials. METHODS: We classified CLE patients as HCQ-responders, HCQ+QC-responders, or HCQ+QC-nonresponders to compare immune profiles. Immunohistochemistry, immunofluorescence, and qRT-PCR were used to characterize inflammatory cells and cytokines in lesional skin. RESULTS: Immunohistochemistry showed that CD69+ T cells were higher in HCQ+QC-nonresponders compared to HCQ- and HCQ+QC-responders (p < 0.05). Immunofluorescence further identified these cells as CD69+CCR7+ circulating activated T cells. Myeloid dendritic cells were significantly higher in HCQ+QC-responders compared to both HCQ-responders and HCQ+QC-nonresponders. Plasmacytoid dendritic cells were significantly increased in HCQ-responders compared to HCQ- and HCQ+QC-nonresponders. No differences were found in the number of autoreactive T cells, MAC387+ cells, and neutrophils among the groups. CLASI scores of the HCQ+QC-nonresponder group positively correlated with CD69+CCR7+ circulating activated T cells (r = 0.6335, p < 0.05) and MAC387+ cells (r = 0.5726, p < 0.05). IL-17 protein expression was higher in HCQ+QC-responders compared to HCQ-responders or HCQ+QC-nonresponders, while IL-22 protein expression did not differ. mRNA expression demonstrated increased STAT3 expression in a subset of HCQ+QC-nonresponders. CONCLUSION: An increased number of CD69+CCR7+ circulating activated T cells and a strong correlation with CLASI scores in the HCQ+QC-nonresponders suggest these cells are involved in antimalarial-refractory skin disease. STAT3 is also increased in HCQ+QC-nonresponders and may also be a potential target for antimalarial-refractory skin disease.

Balanced Free Essential Amino Acids and Resistance Exercise Training Synergistically Improve Dexamethasone-Induced Impairments in Muscle Strength, Endurance, and Insulin Sensitivity in Mice.

Our previous study shows that an essential amino acid (EAA)-enriched diet attenuates dexamethasone (DEX)-induced declines in muscle mass and strength, as well as insulin sensitivity, but does not affect endurance. In the present study, we hypothesized that the beneficial effects will be synergized by adding resistance exercise training (RET) to EAA, and diet-free EAA would improve endurance. To test hypotheses, mice were randomized into the following four groups: control, EAA, RET, and EAA+RET. All mice except the control were subjected to DEX treatment. We evaluated the cumulative rate of myofibrillar protein synthesis (MPS) using 2H2O labeling and mass spectrometry. Neuromuscular junction (NMJ) stability, mitochondrial contents, and molecular signaling were demonstrated in skeletal muscle. Insulin sensitivity and glucose metabolism using 13C6-glucose tracing during oral glucose tolerance tests were analyzed. We found that EAA and RET synergistically improve muscle mass and/or strength, and endurance capacity, as well as insulin sensitivity, and glucose metabolism in DEX-treated muscle. These improvements are accomplished, in part, through improvements in myofibrillar protein synthesis, NMJ, fiber type preservation, and/or mitochondrial biogenesis. In conclusion, free EAA supplementation, particularly when combined with RET, can serve as an effective means that counteracts the adverse effects on muscle of DEX that are found frequently in clinical settings.

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

BACKGROUND: 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). OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical characteristics of itch in cutaneous lupus erythematosus: A prospective, multicenter, multinational, cross-sectional study.

OBJECTIVE: Pruritus is an important symptom frequently accompanying various inflammatory skin conditions and some recent data indicated that it may be associated with autoimmune connective tissue diseases. The aim of this study was to assess the frequency and clinical presentation of itch in CLE. METHODS: A multinational, prospective, cross-sectional study was performed to assess the prevalence, intensity and clinical characteristic of pruritus in various subtypes of CLE. A total of 153 patients with active CLE lesions were included. Their age ranged between 17 and 82 years (mean 49.8 ± 15.4 years), and 115 patients (75.2%) were women. The disease activity and damage were assessed according to the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Pruritus severity was assessed with Numeric Rating Scale (NRS) and the 12-Item Pruritus Severity Scale. Dermatology Life Quality Index and EQ-5D questionnaire were used to measure quality of life. RESULTS: Pruritus was present in 116 (76.8%) of patients of whom half had NRS scoring equal or above 4 points indicating moderate or severe pruritus. Most commonly itch was localized on the scalp, face (excluding ears and nose) and arms (40.5%, 36.2%, 31.9%, respectively). Sensations connected with pruritus were most frequently described as burning, tingling and like ants crawling feeling, but 31.9% patients described it as "pure itch". More than half of patients reported that pruritus was present every day, and it was most frequent during the evenings. The pruritus scoring and the CLASI activity score were significantly correlated (r = 0.42, p = 0.0001), while no correlation was found with the CLASI damage score (p = 0.16). Both the maximum and average itch intensity were correlated with systemic lupus erythematosus (SLE) activity measured with the Systemic Lupus Erythematosus Disease Activity Index. CONCLUSIONS: Pruritus is a common, but frequently overlooked symptom of CLE. Its intensity correlates with the activity of CLE, but not with the skin damage. In more than a half of patients it occurs on a daily basis. The correlation between the intensity of pruritus and the activity of the skin lesions and the systemic involvement indicate that pruritus could be an individual indicator of both SLE and CLE activity.

Gingerenone A Attenuates Monocyte-Endothelial Adhesion via Suppression of I Kappa B Kinase Phosphorylation.

During the early stages of atherosclerosis, monocytes bind and migrate into the endothelial layer, promoting inflammation within the aorta. In order to prevent the development of atherosclerosis, it is critical to inhibit such inflammation. The therapeutic effects of ginger have been investigated in several models of cardiovascular disease. However, although a number of previous studies have focused on specific compounds, the mechanisms of action responsible remain unclear. Here, we investigated five major compounds present in ginger, and observed that gingerenone A exhibited the strongest inhibitory effects against tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) induced monocyte-endothelial adhesion. Furthermore, gingerenone A significantly suppressed the expression of TNF-α and LPS-induced vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 2 (CCL2), key mediators of the interaction between monocytes, and endothelial cells. Transactivation of nuclear factor-κB (NF-κB), which is a key transcription factor of VCAM-1 and CCL2, was induced by TNF-α and LPS, and inhibited by treatment of gingerenone A. Gingerenone A also inhibited the phosphorylation of NF-κB inhibitor (IκB) α and IκB Kinase. Taken together, these results demonstrate that gingerenone A attenuates TNF-α and LPS-induced monocyte adhesion and the expression of adhesion factors in endothelial cells via the suppression of NF-κB signaling. J. Cell. Biochem. 119: 260-268, 2018. © 2017 Wiley Periodicals, Inc.

Interleukin-21 receptor signalling is not critically required for imiquimod-induced psoriasiform dermatitis in mice.

Psoriasis is largely mediated by interleukin (IL)-23/T helper (Th) 17 axis, and IL-21 is a pleiotropic cytokine expressed by Th17 cells. Despite previously reported possible pathogenic roles of IL-21 in human psoriasis, we found that IL-21 receptor (IL-21R) signalling was not crucial for imiquimod-induced psoriatic inflammation, using IL-21R-/- mice. The severity of imiquimod-induced psoriatic manifestation and pro-inflammatory Th17 cytokine levels, IL-17A-producing γδ T cells and CD4+ T cells, and in vitro IL-17A production by γδ T cells after IL-23 stimulation was comparable between wild-type and IL-21R-/- mice. Collectively, IL-21R signalling was not critically involved in IMQ-induced psoriatic inflammation despite an increased IL-21 expression in the IMQ-treated mouse skin. Our data may represent the significant differences between human psoriasis and murine psoriasis model, and further studies using other models will be required to elucidate the role of IL-21 in psoriasis pathogenesis.

Cholesterol Clefts in Basal Cell Carcinoma: An Under-Recognized Association.

Cholesterol clefts have rarely been described in cutaneous tumors other than lipid-rich tumors. However, they seem to be a relatively common phenomenon in basal cell carcinoma (BCC). This study was undertaken to determine the frequency of cholesterol cleft deposition in BCCs, and to identify associated histopathologic and clinical features. Twenty-eight of 249 BCC cases reviewed showed features of cholesterol cleft. Mean disease duration in those with cholesterol cleft was significantly longer than in those without cholesterol cleft (5.58 vs. 3.29 years, respectively; P = 0.013). Sex and age distributions, and average tumor longest diameter (11.6 vs. 9.41 mm) were no different for those with or without cholesterol clefts. The most common anatomical location was the nose in both those with and without cholesterol clefts. BCCs without cholesterol clefts more frequently involved the periauricular and perioral areas, and areas other than the head and neck, such as the trunk and lower extremities (P = 0.087). Histopathologic features of necrosis (26/28, 92.86%), keratinization (19/28, 67.86%), and pigment deposition (18/28, 64.29%) were found to be associated with cholesterol clefts. Cholesterol clefts were intratumorally located in 27/28 cases (96.43%), and stromally located in 2 cases (7.14%); intravascularly located cholesterol clefts were observed in no case. In conclusion, this study shows that cholesterol clefts are relatively common in BCC, and suggests that cholesterol crystal deposition could be associated with longer disease duration and microtrauma.

Cholinergic urticaria: More than a simple inducible urticaria.

BACKGROUND: Cholinergic urticaria (ChU) is characterized by small wheals induced by an elevated core temperature. Its pathomechanism and various aspects of its clinical manifestations are still poorly understood. This study aimed to evaluate the spectrum of symptoms and signs of ChU in Korean patients. METHODS: We retrospectively reviewed the medical records of patients diagnosed with ChU. RESULTS: Among 203 patients (188 male and 15 female), 29 (14%) complained only of an itching or burning sensation without visible skin eruption. The prevalence of ChU was highest in patients in their twenties (56%), while most patients first developed their symptoms during their teens (65%). Patients with a visible skin eruption showed better responses to antihistamines than those without skin lesions. CONCLUSIONS: Physicians should consider the varying manifestations of ChU, including cholinergic pruritus and erythema as minor variants, to provide better management of ChU.

Clinical features of psoriatic arthritis in Korean patients with psoriasis: a cross-sectional observational study of 196 patients with psoriasis using psoriatic arthritis screening questionnaires.

The prevalence and clinical features of psoriatic arthritis (PsA) in psoriasis patients vary widely in different countries, and studies on Korean population are rarely reported. The aim of this study was to investigate the clinical features of PsA in a Korean population of patients with psoriasis by using psoriatic arthritis screening questionnaires. A cross-sectional observational study was conducted, and consecutive psoriatic patients were evaluated for PsA by using two kinds of psoriatic arthritis screening questionnaires: Psoriatic Arthritis Screening and Evaluation tool (PASE) and Psoriasis Epidemiology Screening Tool (PEST). Psoriatic patients with higher score in screening questionnaires were referred to rheumatologist for confirmative diagnosis of PsA. Among 196 psoriasis patients screened by PASE and PEST, total prevalence of PsA was 11.2 % (n = 22/196) with 59.1 % of the cases being newly diagnosed. Compared with patients without PsA, patients with PsA had more extensive psoriasis, higher frequency of pustular and inverse type of psoriasis, and lower frequency of plaque type of psoriasis. Spondylitis was the most common manifestation pattern, followed by polyarthritis, oligoarthritis, predominant distal interphalangeal arthritis, and arthritis mutilans. Our findings are consistent with a low prevalence of PsA among patients with psoriasis in Asia. We also confirm a spondylitis as the most common pattern of PsA in Korea. PsA screening questionnaires can be a simple and useful tool to screen PsA in patients with psoriasis.

Positive reactions to nickel on a patch test do not predict clinical outcome of nickel alloy-based atrial septal defect occluder implantation.

BACKGROUND: Patch testing is thought to be necessary prior to metal device implantation to rule out metal allergy-related complications; however, there are controversies over the effects of nickel allergy on the outcome of nickel alloy-based device implantation. OBJECTIVE: This study aimed to evaluate the adverse events in a Korean population of nickel allergy patients who underwent atrial septal defect (ASD) closure with a nickel-titanium alloy-based device. METHODS: We retrospectively reviewed the medical records of patients who underwent ASD closure with a nitinol device. RESULTS: Among 38 patients who had ASD closure, 4 of 5 nickel-allergic patients and 10 of the 33 non-nickel-allergic patients had post-closure complications. All patients fared well, without device failure culminating in device removal. CONCLUSION: In this study, positive reactions to nickel in a patch test were not associated with adverse early or late outcomes following ASD closure with a nickel alloy-based device.

Development of phage immuno-loop-mediated isothermal amplification assays for organophosphorus pesticides in agro-products.

Two immuno-loop-mediated isothermal amplification assays (iLAMP) were developed by using a phage-borne peptide that was isolated from a cyclic eight-peptide phage library. One assay was used to screen eight organophosphorus (OP) pesticides with limits of detection (LOD) between 2 and 128 ng mL(-1). The iLAMP consisted of the competitive immuno-reaction coupled to the LAMP reaction for detection. This method provides positive results in the visual color of violet, while a negative response results in a sky blue color; therefore, the iLAMP allows one to rapidly detect analytes in yes or no fashion. We validated the iLAMP by detecting parathion-methyl, parathion, and fenitrothion in Chinese cabbage, apple, and greengrocery, and the detection results were consistent with the enzyme-linked immunosorbent assay (ELISA). In conclusion, the iLAMP is a simple, rapid, sensitive, and economical method for detecting OP pesticide residues in agro-products with no instrumental requirement.

Egr-1 is a key regulator of IL-17A-induced psoriasin upregulation in psoriasis.

The early growth response (Egr)-1 is a transcriptional factor which plays an important role in the regulation of cell growth, differentiation, cell survival and immune responses. Emerging evidences including our data demonstrate that the Egr-1 expression is up-regulated in the psoriatic skin lesions. The purpose of this study was to investigate the significance and regulatory mechanism of Egr-1 in the pathogenesis of psoriasis. Through microarray analysis, we found out that psoriasin (S100A7) expression was increased in the Egr-1 overexpressed cells. Our results showed that IL-17A increased Egr-1 expression in the skin of psoriatic patients and cultured human keratinocytes. We then investigated activation of mitogen-activated protein kinase as an upstream signal regulator of Egr-1 expression. IL-17A-induced Egr-1 expression was suppressed by ERK inhibitor. In addition, IL-17A induced psoriasin expression in cultured keratinocytes and the skin of IL-17A intradermally injected mouse. IL-17A-mediated psoriasin upregulation was reduced after treatment of small interfering RNAs against Egr-1. Furthermore, the results of chromatin immunoprecipitation assays demonstrated that Egr-1 directly binds the psoriasin promoter. Our findings present a novel signalling mechanism by which IL-17A can induce the Egr-1-dependent psoriasin expression via the ERK pathway in human keratinocytes. This study suggests that Egr-1 may be a novel and important modulator in IL-17A-mediated immune response in psoriasis.

Dystrophic calcifications after autologous fat injection on face.

Autologous fat injection is widely used procedure for various functional and aesthetic purposes. However, it could result in many immediate or delayed complications including dystrophic calcifications. Almost all of the case reports about dystrophic calcification after autologous fat injection were result from the iatrogenic tissue trauma of breast augmentation. This is a report of a 30-year-old patient who developed pathologically proven multiple dystrophic calcifications on the face after autologous fat injection.

Updates in Dermatomyositis: Newer Treatment Options and Outcome Measures From Dermatologic Perspectives.

Dermatomyositis (DM) is a rare autoimmune connective tissue disease with characteristic skin manifestations and possible muscle involvement. Recent advances in classification system to include skin-predominant subtypes, understanding underlying pathogenic mechanisms and the relationship between clinical phenotypes and myositis-specific autoantibodies have led to development of novel therapeutic options. This corresponds with efforts to develop better outcome measures to accurately catch the patients' current disease status and treatment-induced improvements. This report will review the updates in newer treatments and outcome measures of DM, specifically from a dermatologic point of view.

Unveiling multifaceted roles of myeloid innate immune cells in the pathogenesis of psoriasis.

Psoriasis is a chronic inflammatory skin disease occurring worldwide. Initially viewed as a keratinocyte disorder, psoriasis is now recognized to involve a complex interplay between genetic predisposition, environmental triggers, and a dysregulated immune system, with a significant role of CD4+ T cells producing IL-17. Recent genetic studies have identified susceptibility loci that underscore the importance of innate immune responses, particularly the roles of myeloid cells, such as dendritic cells, macrophages, and neutrophils. These cells initiate and sustain inflammation through cytokine production triggered by external stimuli. They influence keratinocyte behavior and interact with adaptive immune cells. Recent techniques have further revealed the heterogeneity of myeloid cells in psoriatic lesions, highlighting the contributions of less-studied subsets, such as eosinophils and mast cells. This review examines the multifaceted roles of myeloid innate immune cells in psoriasis, emphasizing their functional diversity in promoting psoriatic inflammation. It also describes current treatment targeting myeloid innate immune cells and explores potential new therapeutic strategies based on the functional characteristics of these subsets. Future research should focus on the detailed characterization of myeloid subsets and their interactions to develop targeted treatments that address the complex immune landscape of psoriasis.

Follistatin-like 1 is a myokine regulating lipid mobilization during endurance exercise and recovery.

OBJECTIVE: The aim of this study was to investigate the role of the follistatin-like 1 (Fstl1) and disco-interacting protein 2 homolog A (DIP2a) axis in relation to lipid metabolism during and after endurance exercise and to elucidate the mechanisms underlying the metabolic effects of Fstl1 on adipocytes, considering its regulation by exercise and muscle mass and its link to obesity. METHODS: Twenty-nine sedentary males participated in endurance exercise, and blood samples were collected during and after the exercise. Body composition, Fstl1, glycerol, epinephrine, growth hormone, and atrial natriuretic peptide were measured. 3T3-L1 adipocytes, with or without DIP2a knockdown, were treated with Fstl1 to assess glycerol release, cyclic AMP/cyclic GMP production, and hormone sensitive lipase phosphorylation. The association between DIP2a gene expression levels in human adipose tissues and exercise-induced lipolysis was examined. RESULTS: Fstl1 levels significantly increased during endurance exercise and following recovery, correlating with lean body mass and lipolysis. In 3T3-L1 adipocytes, Fstl1 increased glycerol release, cyclic GMP production, and hormone sensitive lipase activation, but these effects were attenuated by DIP2a knockdown. DIP2a gene expression in human adipose tissues correlated with serum glycerol concentrations during endurance exercise. CONCLUSIONS: Fstl1 is a myokine facilitating lipid mobilization during and after endurance exercise through DIP2a-mediated lipolytic effects in adipocytes.

TLR7-dependent eosinophil degranulation links psoriatic skin inflammation to small intestinal inflammatory changes in mice.

Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.