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Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently closed single-stranded structures lacking 5′–3′ polarity and a polyadenine tail. Over recent years, a growing body of studies have been conducted to explore the roles of circRNAs in human diseases. Systemic lupus erythematosus (SLE) is a severe autoimmune disorder characterized by the presence of autoantibodies and excessive inflammation, which impact multiple organs. Recent advances have begun to shed light on the roles of circRNAs in SLE, providing fresh insights into the pathogenesis of SLE and the latent capacity for translation into clinical applications. Here, we briefly introduce these “star molecules” and summarize their roles in SLE. In addition, we outline the limitations of the current studies and raise prospects for future research., Graphical abstract, This review provides an overview of the current knowledge of circRNA biology, with a particular emphasis on their roles and future perspectives in SLE. The research ideas about the expression, transmission, function, and mechanism of circRNAs are not only suitable for SLE but also generally suitable for other autoimmune diseases.

The skin is an absorptive organ, targeted in the transdermal delivery system. The microneedle method is an updated approach to deliver compounds through the skin in an efficient way. A microneedle patch is composed of dozens to hundreds of micron-sized needles with various structures and advantages benefiting from their special and smart designs. The microneedles method is much more superior to those traditional transdermal delivery ways because of advantages such as minimally invasive, painless, convenience, and improved patient compliance. Up to now, the microneedles field has developed rapidly and is divided into four major types by researchers: solid microneedles (SMNs), hollow microneedles (HMNs), dissolving microneedles (DMNs), and coated microneedles (CMNs). Every type of these microneedles has different advantages according to their unique properties and designs. Psoriasis is a polygenic chronic dermatological disease with no cure, and the treatment is based on symptom control. The traditional therapeutic method is diverse, embracing topical drugs, systemic drugs, physical therapy, etc. With the limitation of present drug delivery, the demand for new delivery methods for psoriasis is in the spotlight. Thus, this review paper aims to provide a comprehensive statement about the microneedles, the progress of the microneedle application in the management of psoriasis and the clinical challenges.

Psoriasis is a chronic immune-mediated skin disease affecting multiple systems, and tumor necrosis factor-α (TNF-α) plays a significant role in the initiation and progression of the disease process. Psoriasis has a high prevalence rate in the Western world, especially in the USA and Australia; in China, although the prevalence rate is much lower, there is still a large number of patients suffering from psoriasis and its comorbidities. As TNF-α is thought to be crucial in the pathogenesis of psoriasis, specific therapy blocking TNF-α may be beneficial in the treatment of this disease. Infliximab, a murine-human monoclonal antibody, is highly efficacious in the treatment of moderate-to-severe psoriasis, with better skin clearance and faster onset of action than topical medications such as methotrexate, narrow-band ultraviolet B, and calcipotriol. Lack of adherence to infliximab therapy is mainly due to loss of response (LOR) over time and adverse events, particularly because infusion reactions are usually encountered. Anti-infliximab antibody is thought to be responsible for the LOR and infusion reactions. However, the mechanism underlying the formation of anti-infliximab antibody and its side effects remains unclear. Further studies identifying patients at risk for LOR will probably help clinicians to select the right patients for anti-TNF-α therapy and to increase the durability of the treatment. This review discusses the efficacy of infliximab as demonstrated by various clinical trials, LOR to infliximab, combatting LOR, as well as the adverse events usually faced during the use of infliximab therapy and the infliximab biosimilar Remsima®. We hope that we can discover a better way to use infliximab in the therapy of psoriasis from the current research data.

Background Fargesin is commonly used in the treatment of allergic rhinitis, inflammation, sinusitis and headache. Objective The aim of the study is to investigate a new function of fargesin against melanin production and its underlying molecular mechanism. Methods B16F10 mouse melanoma cells, Melan-a and human epidermal melanocytes were treated with different concentrations of fargesin for the indicated time. The extracellular and cellular melanin content was detected by spectrometry at 490 nm and 405 nm, respectively. RT-qPCR and Western blot analysis were used to exam the expression of melanogenic enzymes and the activities of PKA/CREB and p38 MAPK pathway components. Zebrafish was used as an in vivo model for studying the function of fargesin in regulating melanogenesis. Results Fargesin effectively inhibited melanin production at moderate dose in mouse B16F10 melanoma cells, normal melanocyte cell lines and zebrafish. The expression of microphthalmia-associated transcription factor (MITF), its downstream melanogenic enzymes and tyrosinase activity were also strongly reduced by fargesin. Moreover, the increase of melanin production induced by UVB and forskolin could be fully reversed by fargesin treatment. Fargesin also effectively inhibited the activation of PKA/CREB and p38 MAPK as well as their interactions, which in turn is responsible for the expression of MITF and melanogenic enzymes. Conclusions These results show that fargesin can function as an anti-melanogenic agent, at least in part, by inhibiting PKA/CREB and p38/MAPK signaling pathways. Therefore, fargesin and its derivatives may potentially be used for preventing hyperpigmentation disorders in the future.

Psoriasis is an immune-related chronic skin disease, and interleukin-22 (IL-22) is involved in psoriasis pathogenesis through promoting proliferation and migration abilities of keratinocytes. Here, we analysed the role of circular RNA (circRNA) RAB3B, member RAS oncogene family (circRAB3B) in regulating the phenotypes of IL-22-induced HaCaT cells.RT-qPCR was implemented to assess RNA abundance. Western blot assay was adopted to assess protein abundance. Cell proliferation capacity was examined by cell counting kit-8 (CCK8) assay and 5-ethynyl-2'-deoxyuridine (Edu) assay. Cell motility was assessed by transwell assays and wound healing assay. Flow cytometric analysis was utilized to evaluate cell cycle progression and apoptosis. The intermolecular binding relations were tested via dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. CircRAB3B expression was reduced in psoriatic cutaneous specimens and IL-22-treated HaCaT cells.CircRAB3B overexpression hampered the proliferation, motility, and cell cycle progression and elevated the apoptotic rate of IL-22-treated HaCaT cells, and circRAB3B silencing exhibited opposite effects in IL-22-induced HaCaT cells. CircRAB3B acted as microRNA-1228-3p (miR-1228-3p) sponge in HaCaT cells, and miR-1228-3p overexpression largely overturned circRAB3B overexpression-induced effects in HaCaT cells. MiR-1228-3p interacted with phosphatase and tensin homolog (PTEN), and circRAB3B sponged miR-1228-3p to induce PTEN level. MiR-1228-3p accumulation-mediated effects were partly alleviated by PTEN overexpression in HaCaT cells upon IL-22 treatment.CircRAB3B suppressed psoriasis progression partly through down-regulating miR-1228-3p and up-regulating PTEN.

Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here, we show that the expression of Ovol1 (encoding ovo-like 1 transcription factor) is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod. Using bulk and single-cell RNA sequencing, we identify molecular changes in the epidermal, fibroblast, and immune cells of Ovol1-deficient skin that reflect an altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1α signaling in the microenvironment of imiquimod-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for OVOL1 in curtailing psoriasis-like inflammation and the associated skin pathology.

Psoriasis is an immune-mediated chronic inflammatory skin disease primarily mediated by the activation of interleukin (IL)-17-producing T cells. Traditional Chinese Medicine (TCM) represents one of the most effective complementary and alternative medicine (CAM) agents for psoriasis, which provides treasured sources for the development of anti-psoriasis medications. Xiao-Yin-Fang (XYF) is an empirically developed TCM formula that has been used to treat psoriasis patients in Shanghai Changhai Hospital for over three decades. Imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was utilized to investigate the therapeutic effects of XYF by the assessment of disease severity and skin thickness. Flow cytometric assay was performed to explore the influence of XYF on skin-related immunocytes, primarily T cells. And, RNA sequencing analysis was employed to determine the alternation in gene expression upon XYF therapy. We discovered that XYF alleviated psoriasis-like skin inflammation mainly through suppressing dermal and draining lymph-node IL-17-producing γδT (γδT17) cell polarization. Moreover, XYF therapy ameliorated the relapse of psoriasis-like dermatitis and prohibited dermal γδT cell reactivation. Transcriptional analysis suggested that XYF might regulate various inflammatory signaling pathways and metabolic processes. In conclusion, our results clarified the therapeutic efficacy and inner mechanism of XYF therapy in psoriasis, which might promote its clinical application in psoriasis patients and facilitate the development of novel anti-psoriasis drugs based on the bioactive components of XYF.

Psoriasis is a chronic, systemic disease that requires long-term management. Biologic agents have been used widely against psoriasis, such as infliximab. We analyzed the survival and discontinuation rates of infliximab when treating psoriasis under real-world conditions in China. Patients with moderate-to-severe psoriasis treated with infliximab in Shanghai Skin Disease Hospital from January 2015 to April 2020 were included in our retrospective study. Information from their medical records (clinical characteristics, Psoriasis Area Severity Index [PASI] score, laboratory results, and time of discontinuation) was collected through the Shanghai Skin Disease Hospital database. The survival of infliximab was assessed with Kaplan-Meier plots and multivariate Cox regression. Forty-two patients who underwent treatment were assessed retrospectively (38.1% had been diagnosed with psoriatic arthritis [PsA]). The discontinuation rate was 57.1%, the mean survival time of discontinuation was 57 weeks for patients with PsA vs 69 weeks for those without PsA (P = .5993). The cholesterol level (P = .003) and lymphocyte percentage (P = .010) were associated with longer survival of infliximab according to Cox regression analysis. Our study revealed that infliximab had a similar drug survival as previous studies, the high cholesterol level and lymphocyte percentage might function as negative predictor for infliximab persistence.

It is known that LGR4 plays an important role in hair follicle (HF) development, but the impact of LGR4 on the hair cycle is still unclear. In this study, we have found that K14-Cre–mediated skin epithelia–specific deletion of Lgr4 results in delayed anagen entry during the physiological hair cycle and compromised HF regeneration upon transplantation. We show that, although Lgr4 deletion does not appear to affect the number of quiescent HF stem cells, it leads to reduced numbers of LGR5(+) and actively proliferating stem cells in the HFs. Moreover, LGR4-deficient HFs show molecular changes consistent with decreased mTOR and Wnt signaling but upregulated BMP signaling. Importantly, the reactivation of the protein kinase B pathway by injecting the protein kinase B activator SC79 in Lgr4(−/−) mice can effectively reverse the hair cycle delay. Together, these data suggest that LGR4 promotes the normal hair cycle by activating HF stem cells and by influencing the activities of multiple signaling pathways that are known to regulate HF stem cells. Our study also implicates LGR4 as a potential target for treating hair disorder in the future.

Psoriasis is a common chronic skin disease characterized by epidermal proliferation and inflammation. Pustular psoriasis (PP) is one of the most serious and refractory. The number, differentiation, and function of B10 cells in patients with PP were analyzed, and the relationship between B10 cells and PP, an autoimmune disease, was explored. We established an Imiquimod psoriasis mouse model and subcutaneously injected B10 cells as treatment. We found that the proportion of B10 cells in the peripheral blood of patients with PP was lower than that of the normal controls. However, the number of B10 precursor cells increased. B10 cells in the peripheral blood may be mobilized to effector sites, such as the skin. In patients with PP, B10 cells do not display evident developmental disorders under the CD40 and TLR9 pathways. Normal human B10 cells were found to inhibit the secretion of IFN-γ and TNF-α by lymphocytes significantly. Whereas the function of B10 cells in patients with PP is impaired, and the inhibition is not apparent. Treatment with a B10 cells injection displays a certain therapeutic effect on PP. This study enriched the etiology and pathogenesis of PP. It provides a foundation for cell therapy for the treatment of autoimmune diseases.

Background The Dangguikushen (DGKS) pill is a proprietary traditional Chinese medicine that has shown superior efficacy in the treatment of acne vulgaris for many years. Methods A network pharmacology-based analysis was performed to explore the potential anti-acne compounds, core therapeutic targets, and the main pathways, involved in the DGKS pill bioactivity. The matching results between the predicted targets of the DGKS pill and the well-known targets of acne vulgaris were collected, followed by network establishment using protein-protein interaction (PPI) data. Cytoscape was utilized to analyze the network and screen the core targets. Furthermore, the Database for Annotation, Visualization and Integrated Discovery (DAVID), and ClueGO were used for the enrichment analysis of the Kyoto Encyclopedia of Genes and Genomics (KEGG) pathways and Gene Ontology biological processes (GO-BP). Finally, the "compound-target-pathway" network was constructed. Results This approach identified 19 active compounds, 46 therapeutic targets and 12 core therapeutic targets of the DGKS pill. The biological processes were primarily related to reactive oxygen species (ROS) metabolic process, gland morphogenesis, and female gonad development. The DGKS pill was significantly associated with eight pathways including the PI3K-Akt, TNF, NF-kappa B, and p53 signaling pathways. Conclusion DGKS pill might have a synergistic effect on the inhibition of excessive sebaceous lipogenesis and sebocyte differentiation, and likewise, anti-inflammatory effects via the different signaling pathways (PI3K-Akt, TNF, NF-kappa B, and p53). This article is protected by copyright. All rights reserved.

Cutaneous metastasis from primary visceral malignancy is a relatively uncommon clinical entity, with a reported incidence ranging from 0.22% to 12% of all malignancies. Here we report a 64-year-old asymptomatic female patient with Peutz-Jeghers syndrome presenting with multiple scalp metastases as the initial manifestation secondary to lung adenocarcinoma. Subsequent lung computed tomography scan showed large masses involving the left upper lobe associated with extensive mediastinal lymphadenopathy. After treatment with an epidermal growth factor receptor inhibitor gefitinib, the size of the tumor in the lung reduced significantly and the condition of the patient also gradually improved. Our case demonstrated that scalp metastasis could be the first sign of an internal malignancy. Asymptomatic elderly patients presenting with multiple, painless, immobile cutaneous nodules should be considered for further investigations to rule out the underlying primary cause. Metastasis to the skin is often a preterminal event that heralds poor prognosis.

Numerous biologics are currently licensed for the treatment of psoriasis, including new drugs targeting interleukin-17 (IL-17) and interleukin-23 (IL-23). This meta-analysis evaluated the short-term (12-16 weeks) efficacy and safety of biologics targeting IL-17 and IL-23 in the treatment of moderate-to-severe plaque psoriasis. Twenty-one randomized clinical trials met the defined inclusion criteria. Our results showed that Ixekizumab (160 mg wk0 + 80 mg q2w) had the greatest probability of achieving both PASI 75 (RR 21.32, 95% CI 15.48-29.36, P < 0.00001) and PASI 90 response (RR 59.76, 95% CI 32.41-110.19, P < 0.00001) at the primary endpoint times, followed by Ustekinumab and Secukinumab. Regarding the safety profile, Tildtakizumab (200 mg, q4w) was safest (RR 0.88, 95% CI 0.78-0.99, P = 0.04), while Ixekizumab (160 mg wk0 + 80 mg q2w) showed highest risk for one or more AE (RR 1.26, 95% CI 1.15-1.38, P < 0.00001). However, there was no significant difference between the two biologics regarding one or more SAEs. Comparing to the biologics targeting IL-23, the pooled effect size favored the biological agents targeting IL-17 in terms of the PASI 75 (PASI 75: RR 17.28, 95% CI 14.51-20.58, P < 0.00001) and PASI 90 (RR 37.19, 95% CI 26.91-51.41, P < 0.00001). The rate of overall AEs was significantly higher (P < 0.00001) in biologics targeting the IL-17 (RR 1.18, 95% CI 1.12-1.24, P < 0.00001) compared to biologics targeting IL-23 (RR 0.97, 95% CI 0.91-1.04, P = 0.44), and with respect to one or more SAEs, no difference was seen between biologics targeting IL-17 and IL-23. This meta-analysis found that Ixekizumab was the most effective short-term treatment, but was ranked as the most risk therapeutic choice among the biologics involved in this study, while Tildtakizumab was the best alternative in the case of safety. Furthermore, it demonstrated that biologics inhibiting IL-17 were superior to biologics targeting IL-23 in terms of the efficacy, but posed higher risk at the same time. This study might help the clinicians and guideline developers to choose the optimal one among these biologics for the treatment of moderate-to-severe plaque psoriasis.

This study evaluated safety and efficacy of onabotulinumtoxinA for moderate to severe glabellar lines (GL) following laser therapy in Chinese subjects.Subjects (n = 173) were followed for 120 days following a single onabotulinumtoxinA (20 U) treatment for GL after recent laser therapy. Subjects completed validated patient-reported outcomes, including Facial Lines Outcome 11-item (FLO-11) Questionnaire and Facial Lines Satisfaction Questionnaire (FLSQ). Physicians and subjects assessed GL severity at maximum frown and at rest using the Facial Wrinkle Scale with Asian Photonumeric Guide (FWS-A).Mean total FLO-11 scores increased from 47.7 (baseline) to 75.9 (day 120) (p 0.0001), with mean improvement of at least two grades for most items maintained to day 120. Most subjects were mostly or very satisfied, per the FLSQ. Percentages of subjects with at least one-grade improvement in FWS-A (responders) at maximum frown per subjects and physicians were 93.1% and 97.1%, respectively, at day 30, and 72.3% and 81.5% at day 120 (all, p 0.0001). More than 70% were FWS-A responders at day 120. All adverse events were mild or moderate; none were related to onabotulinumtoxinA.A single onabotulinumtoxinA (20 U) treatment following laser therapy was safe and effective in correcting GL for up to 120 days.

Psoriasis is an immune-mediated polygenic inherited skin disease. Many biologic agents have been approved for the treatment of moderate-to-severe plaque psoriasis. The most commonly utilized biologics include TNF-α antagonists (etanercept, infliximab, and adalimumab), IL-12/23P40 antagonist (ustekinumab), IL-23P19 antagonist (guselkumab), IL-17A antagonist (secukinumab and ixekizumab), and IL-17RA antagonist (brodalumab). However, some patients may fail to respond well to their first biologic agent. Reasons for failure include primary failure (lack of initial efficacy), secondary failure (loss of efficacy over time) or the development of adverse effects. For patients desiring maximum skin clearance and better quality of life, switching to a second biologic agent might be a worthwhile option. This review discusses recent clinical studies on switching therapies in treating psoriasis, and found that switching biologic agents can significantly improve outcomes for patients. Some clinical guidelines are also discussed. This research provides some advice on establishing individualized treatment regimens based on clinical needs and pharmacologic characteristics.

The coronavirus disease 2019 (COVID-19) outbreak affects the use of biologics for psoriatic patients, in the way that the consequential immunosuppression potentially alters a patient's susceptibility to the virus or deteriorate the condition if the patient is infected or even change the prognosis of infection. Therefore, authors reviewed currently available recommendations from international psoriasis academic organizations and specialists, and summarized them with the specific situation in China. We are trying to provide guidance to the use of biologics for psoriatic patients in the following contexts: patients on biologic therapy, patients being considered for biologic therapy initiation, patients with low-risk or high-risk of SARS-CoV-2 coronavirus infection, patients tested negative or positive for the nucleic acid testing of virus. © 2021 Lippincott Williams and Wilkins. All rights reserved.

The glucose homeostasis is essential for brain function, and energy deficiency is a key feature of brain aging. We investigated whether improving glucose metabolism in the auditory cortex can delay the aging of auditory function of guinea pigs with age-related hearing loss (ARHL) by d-galactose. Auditory function was assessed by auditory brainstem response (ABR), glucose metabolism was detected by micro PET/CT, and the proteome were identified in auditory cortex by two-dimensional electrophoresis and matrix assisted laser desorption/ionization mass spectrometry. Glucose metabolism decreased in the auditory cortex of d-galactose group, and improving glucose metabolism can delay the aging of auditory function by upregulating seven metabolism-related proteins including ATP synthase subunit beta, triosephosphate isomerase, creatine kinase U-type, pyruvate dehydrogenase E1 component subunit beta, alpha-enolase, phosphoglycerate kinase, and tubulin beta-2A chain. These results suggest that the decrease of glucose metabolism in the auditory cortex may be an important role in the aging of auditory function, and improving glucose metabolism in the auditory cortex can delay the aging of auditory function of guinea pig with ARHL induced by d-galactose.

Background Previous psoriasis studies have mostly focused on skin-related immunology, but the exact mechanisms remain elusive. Clinical evidence, such as higher morbidity among obese individuals and emotional factors, indicate that psoriasis is a complex systemic disease. High-throughput transcriptome analysis provides an effective method to comprehensively assess the disease. Objective The present study is aiming to understand transcriptome changes of clinical psoriasis skins and comprehensively assess the diseases using pathways analysis. Methods We performed transcriptome sequence of clinical psoriatic samples. Biological pathway analyses were conducted using differentially expressed RNAs, as well as identified competing endogenous RNAs (ceRNAs). qRT-PCR and histological immunofluorescence staining was conducted to verify the differentially expressed RNAs (DE_RNAs) and the three important enriched biological pathways. Results Numerous DE_RNAs were identified between psoriasis patients and healthy people. Functional analysis indicated PPAR-fatty acids metabolism pathways, neural-hormone regulations, circadian entrainment were the three mostly appeared pathways. For PPAR-fatty acids metabolism pathways, the expression of seven randomly selected genes, including ACSBG1, ACOT2), CYP27A1, ELOVL3, FABP7, FADS2 and PPARG were all significantly decreased in psoriasis lesions. For neural-hormone regulation pathways, the expression of CFL1, EPHA2, HRAS were all significantly upregulated in psoriasis lesions. While the expression of four randomly selected genes from circadian entrainment pathways, including CRY2, PER3, NR1D1 and RORC were all significantly downregulated. Histological immunofluorescence staining of FADS2, EPHA2 and CRY2 were consistent with their genes’ expressions. Conclusion Our results revealed transcriptome changes of psoriasis, and indicated three important pathways involved in psoriasis, including PPAR-fatty acids metabolism pathways, neural-hormone regulations, circadian entrainment.

Psoriasis is a chronic inflammatory skin disorder that impairs the quality of life of affected patients. Emerging studies indicate that certain long non-coding RNAs (lncRNAs) have important roles in psoriasis. However, the exact functions of lncRNAs and their regulatory mechanisms as competitive endogenous RNAs (ceRNAs) in psoriasis have remained to be fully elucidated. In the present study, differentially expressed lncRNAs, microRNAs (miRNAs) and mRNAs were identified by analyzing public datasets, and a psoriasis-associated lncRNA-miRNA-mRNA network was constructed based on the ceRNA theory. Furthermore, previously validated abnormally expressed miRNAs in psoriasis were identified by a systematic literature search in the PubMed and Web of Science databases, and a specific miRNA-associated lncRNA-miRNA-mRNA sub-network was extracted. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using DAVID 6.8. A total of 253 lncRNAs, 106 miRNAs and 1,156 mRNAs were identified as being differentially expressed between psoriasis skin and healthy control skin. The present study identified two key lncRNAs that may potentially have a role in the pathogenesis of psoriasis: AL035425.3 and Prader Willi/Angelman region RNA 6. This integrative analysis enhances the understanding of the molecular mechanism of psoriasis and may provide novel therapeutic targets for the treatment of psoriasis.

Psoriasis is a chronic inflammatory skin disease with unclear pathogenesis. Interleukin‐33 (IL‐33) is highly expressed in patients with psoriasis, but its role in psoriasis is unknown. The aim of this study was to investigate the possible role of IL‐33 in the pathogenesis and treatment of psoriasis. IL‐33 expression was determined using enzyme‐linked immunosorbent assay, real‐time fluorescent quantitative polymerase chain reaction and immunohistochemical staining. CD4(+) T cells were sorted using magnetic beads and treated with or without IL‐33. Imiquimod (IMQ) was used to induce psoriatic inflammation in mice. The frequency of immune cells was determined using flow cytometry. The cytokine level in mouse skin was measured using cytometric bead array. Our results showed that IL‐33 was highly expressed in the lesional skin and serum of patients with moderate‐to‐severe plaque psoriasis. IL‐33 inhibited the expression of IL‐17 in CD4(+) T cells of psoriasis patients. Subcutaneous injection of IL‐33 alleviated the IMQ‐induced psoriatic inflammation in mice, reduced tumor necrosis factor‐α and IL‐23 expression, and decreased the proportion of T helper type 17 (Th17) cells in the skin‐draining lymph nodes in the mice. Our results suggest that IL‐33 plays a protective role in the pathogenesis of psoriasis by suppressing Th17 cell differentiation and function. The potential therapeutic effect of IL‐33 in treating psoriasis warrants further investigation.

Phaeohyphomycosis, caused by opportunistic rare fungi, has increasingly been reported in diabetic and immunosuppressed patients. Pyrenochaeta unguis-hominis (P. unguis-hominis), a member of the dematiaceae group, has been identified to cause human nail infection. We report a rare case of cutaneous phaeohyphomycosis in a diabetic female caused by P. unguis-hominis.

Background Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation. Ginsenoside compound K (CK), a bioactive metabolite of ginseng, modulates various skin disorders with an impact on keratinocyte biology. However, the effect of Ginsenoside CK in psoriasis has not been explored. Objective Our aim was to investigate whether ginsenoside CK could affect the homeostasis of keratinocytes and their expression of psoriasis-associated antimicrobial protein regenerating islet-derived protein 3-alpha (REG3A) and its murine ortholog RegIIIγ. We further explored the therapeutic potential of ginsenoside CK in imiquimod (IMQ)-induced psoriasis-like dermatitis. Methods The effects of ginsenoside CK in cell growth and apoptosis of human keratinocytes were measured by MTT assay and flow cytometry, respectively. Bax levels were evaluated by Western blot in HaCaT cells following ginsenoside CK stimulation. REG3A levels were assessed by RT-PCR and Western blot in human keratinocytes following interleukin (IL)-36γ and ginsenoside CK co-simulation. Utilizing IMQ-induced psoriasis mouse model, the therapeutic effects of 0.1% and 1% ginsenoside CK cream were assessed by skin thicknesses and histological examinations, and RegIIIγ level in the lesional skin was detected by Western blot and immunofluorescence. Results Ginsenoside CK prohibited human keratinocyte proliferation but did not affect their apoptosis. Moreover, it inhibited IL-36γ-induced REG3A expression in HaCaT cells. Ginsenoside CK alleviated imiquimod-induced psoriasis-like hyperkeratosis and reduced RegIIIγ expression in the keratinocytes from lesional skin. Conclusion Ginsenoside CK ameliorated IMQ-induced psoriasis-like dermatitis possibly through inhibiting REG3A/RegIIIγ expression in keratinocytes, which highlighted a therapeutic potential of ginsenoside CK in psoriasis.

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease, with over-activated interleukin (IL)-17-producing CD4+ T cells (Th17) and repressed regulatory T (Treg) cells. IL-21 is a Th17-related cytokine and plays an important role in the pathogenesis of psoriasis. However, the mechanism by which IL-21 affects the pathogenic progress of psoriasis remains poorly understood. Methods: IL-21 and IL-21 receptor (IL-21R) expression in normal and psoriatic lesional skin were determined by immumohistochemical staining, immunofluorescence staining, and western blotting. The levels of IL-21, IL-17A, and IL-22 in the culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-10 in the culture supernatants was measured by cytometric bead array (CBA). The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). CD4+ T cells were isolated from the peripheral blood mononuclear cells (PBMCs) from the psoriasis patients and healthy individuals and then treated with or without IL-21 for 3 days. The proportions of Th17 and Treg cells were determined by flow cytometric analysis. Results: IL-21 and IL-21R were highly expressed in the lesional skin and peripheral blood of psoriasis patients. IL-21 promoted CD4+ T cells proliferation and Th17 cells differentiation and inhibiting Treg cells differentiation by upregulating RORγt expression and downregulating Foxp3 expression, with increased expression and secretion of IL-17A and IL-22. The proportion of Treg cells was negatively correlated with that of Th17 cells in psoriasis patients. Conclusion: Our results suggest that IL-21 may promote psoriatic inflammation by inducing imbalance in Th17 and Treg cell populations.

Background Psoriasis is a T cell–mediated autoimmune skin disease. Accumulating evidence has demonstrated that co-inhibitory receptors (CIRs) play a vital role in regulating T cell–mediated immune response, especially in neoplasm and autoimmunity. However, the immuno-function of CIRs in the development of psoriasis remains unclear. Objective We investigated the expression of CIRs on the circulating T lymphocytes of psoriasis patients before and after anti–tumor necrosis factor-α (TNF-α) therapy. Methods We enrolled 17 patients with moderate-to-severe plaque psoriasis, 17 patients with mild plaque psoriasis, and 18 healthy controls in this study. Fourteen of the moderate-to-severe psoriasis patients were treated with infliximab, a monoclonal antibody against TNF-α. Peripheral blood was collected, and peripheral blood mononuclear cells were extracted. The proportion of T cell subsets along with their expression of CIRs, namely T cell immunoreceptor with Ig and ITIM domains (TIGIT), lymphocyte activating gene 3 (LAG-3), cytotoxic T–lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte–associated protein (BTLA), endothelial protein C receptor (PROCR), podoplanin (PDPN), programmed cell death 1 (PD-1), and T cell immunoglobulin mucin family containing molecule 3 (TIM-3), were determined by flow cytometric assay. Results The moderate-to-severe plaque psoriasis patients had less circulating Tregs, which increased after infliximab treatment. They also had decreased TIGIT, LAG-3 but increased PDPN expression on peripheral CD4+ T cells. Infliximab enhanced TIGIT, LAG-3, CTLA-4 but reduced PROCR expression on circulating CD4+ T cells. Remarkably, both the frequency of circulating Tregs and the expression level of TIGIT on CD4+ T cells at baseline (pre-treatment) negatively correlated with the extent of PASI score reduction benefited from infliximab therapy. Conclusion Anti–TNF-α therapy increased the frequency of Tregs and TIGIT, LAG-3, CTLA-4 expression but reduced PROCR expression on circulating CD4+ T cells in psoriasis patients. The baseline proportion of Tregs and the expression level of TIGIT on circulating CD4+ T cells might serve as predictive markers for the degree of disease remission benefited from infliximab treatment.

Breast cancer is the leading cause of cancer-related death among women, with a more 20% 5-year survival rate after metastases. It is therefore critical to improve early diagnosis in order to improve disease prognosis. This study investigates cytokine profiles of breast cancer serum with the aim of identifying biomarkers for early diagnosis. A solid-phase antibody array was used for screening 274 biomarkers in serum from breast cancer patients. ELISA assay was carried out to identify biomarkers with differential expression. The serum levels of IL-8, MIP-1 alpha, MIP-1 beta, MMP-8, Resistin, FLRG, and BCAM were significantly higher in breast cancer patients, but LAP and TSH-β levels were lower. ELISA assay results confirmed those of the antibody array. Our results suggest that these cytokines, screened by antibody array, might serve as novel inflammatory markers in breast cancer patients. Whether these biomarkers are specific for breast cancer and can help to improve diagnoses and prognoses of breast cancer needs further investigation.

Psoriasis is a chronic inflammatory disease whose etiology is multifactorial. The contributions of cellular metabolism to psoriasis are unclear. Here, we report that interleukin-17 (IL-17) downregulated Protein Phosphatase 6 (PP6) in psoriatic keratinocytes, causing phosphorylation and activation of the transcription factor C/EBP-β and subsequent generation of arginase-1. Mice lacking Pp6 in keratinocytes were predisposed to psoriasis-like skin inflammation. Accumulation of arginase-1 in Pp6-deficient keratinocytes drove polyamine production from the urea cycle. Polyamines protected self-RNA released by psoriatic keratinocytes from degradation and facilitated the endocytosis of self-RNA by myeloid dendritic cells to promote toll-like receptor-7 (TLR7)-dependent RNA sensing and IL-6 production. An arginase inhibitor improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle hyperreactivity and excessive polyamine generation in psoriatic keratinocytes promote self-RNA sensation and PP6 deregulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis.

Etanercept has greatly improved management considerably. However, the efficacy and safety of combination therapy with methotrexate and the mechanism of action are not known. We aimed to describe the use of combined therapy of etanercept and methotrexate against moderate-to-severe plaque psoriasis in a Chinese population. We also wished to study the changes in expression of pro-inflammatory factors in peripheral blood mononuclear cells (PBMCs) and serum after the treatment to ascertain the mechanism of action. Thirty patients with moderate-to-severe plaque psoriasis were assigned into a monotherapy group and combination group randomly and equally. All patients received etanercept (50 mg, s.c., weekly), whereas patients in the combination group also received oral methotrexate (7.5-15 mg, p.o., weekly). Serum levels of interleukin (IL)-17A, IL-23, tumor necrosis factor (TNF)-α and their mRNA expressions in PBMCs were measured by ELISA and qRT-PCR. In the monotherapy group, Psoriasis Area and Severity Index (PASI) 50/75/90 responses were achieved by 86.7/66.7/40% after 24 weeks of treatment whereas, in the combination group, they were achieved by 93.3/80/60%, respectively. Although the overall prevalence of adverse effects (AEs) was higher in the combination group (60%) than in the monotherapy group (33.3%), the AEs were mild to moderate. The serum levels of IL-17A, IL-23, TNF-α, IL-33 and their mRNA expression in the PBMCs of the two groups were significantly higher than those of healthy controls (P < 0.05). Compared with the monotherapy group, serum levels of IL-17A, IL-23, TNF-α and their mRNA expression in PBMCs were decreased significantly in the combination group (P < 0.05). These data suggest that the efficacy of etanercept could be improved upon combination with methotrexate in the treatment of moderate-to-severe plaque psoriasis without increasing the risk of serious AEs. The mechanism of action might be associated with down-regulation of IL-17A, IL-23, and TNF-α.

A 64 year old woman presented with two weeks of redness, pain, swelling, and exudation of the periungual skin around all fingernails and toenails. Examination found she had complete destruction over the nailfolds, and the periungual skin was erythematous with blisters (fig 1). Fig 1 Damage over the nail folds of finger and toenails She was treated for bacterial and fungal paronychia without any improvement, and the results of fungal microscopy and culture of periungual skin were negative. Two weeks later, she developed cutaneous blisters/bullae on the trunk, which were thinly walled and relatively flaccid. The rest of the skin became fragile, and light stroking caused the epidermis to …

Mesenchymal Stem Cells (MSCs) represent a heterogeneous group of self-renewal, multipotent non-hematopoietic stem cells, which display profound immunomodulatory functions and promising therapeutic effects. Autoimmune diseases, which result from an aberrant immune response to selfantigens, can be detrimental to nearly all body tissues. With the advance in developing a novel treatment, including biological agents, it is still impossible to cure autoimmune disorders. Recent studies demonstrate the remarkable therapeutic effectiveness of MSCs towards a wide array of autoimmune diseases. In this review, the immunomodulatory influence of MSCs over immune cells and the application of MSCs transplantation in treating autoimmune diseases are highlighted.

T helper 17 (TH17) cells and interleukin-17A (IL-17A) produced by them are critical in autoinflammatory diseases, such as psoriasis. IL-17A has been shown to signal through IL-17 receptor A/IL-17 receptor C (IL-17RA/IL-17RC) complex to drive inflammatory responses. However, in a psoriasis model, we found that Il17rc deficiency did not completely ameliorate the disease, suggesting another receptor. In search for another IL-17A-interacting receptor, we found that IL-17RD directly bound IL-17A but not IL-17F or IL-17A/F heterodimer and formed a heterodimer with IL-17RA. IL-17A-, but not IL-17F- or IL-17A/F-, mediated gene expression was defective in Il17rd-deficient keratinocytes. Il17rd deficiency in nonhemopoietic cells attenuated imiquimod-induced psoriasis-like skin inflammation. Although IL-17RC and IL-17RD differentially activated IL-17A-dependent signaling and gene expression, their compound mutation led to complete deficits in keratinocytes. IL-23 was found induced by IL-17A in keratinocytes, dependent on both IL-17RC and IL-17RD, suggesting feed-forward regulation of IL-23/IL-17 axis in psoriasis. Together, IL-17RD constitutes a second functional receptor for IL-17A and, together with IL-17RC, mediates the proinflammatory gene expression downstream of IL-17A.

Although standard itraconazole pulse therapy is a well-established regimen for toenail onychomycosis, the cure rate for onychomycosis remains low. To evaluate the efficacy and safety of different cycles of itraconazole pulse therapy, determine the optimal dosage and number of cycles for onychomycosis. A total of 90 outpatients of our hospital with onychomycosis were randomised into three treatment groups: (1) standard itraconazole pulse therapy (200 mg twice per day, 1 week each month for three pulses); (2) long-term pulse therapy (200 mg twice per day, 1 week each month for six pulses); (3) low-dose and long-term pulse therapy (200 mg/d, 1 week per month for six pulses) and were followed up for 15 months. Of the initial patients, the trial was completed by 81 patients. The complete cure rates were 32.43% for three cycles and 75% for six cycles (P

Psoriasis is an autoimmune disease involving the excessive proliferation of keratinocytes mediated by T-cells. Parathyroid hormone (PTH) has been identified as an essential factor in the treatment of psoriasis. In the present study, the mechanism underlying the effect of recombinant human parathyroid hormone (rhPTH) (1-34) in keratinocytes was investigated. The effects of rhPTH (1-34) on cell proliferation, cell cycle, and the secretion and expression of C-X-C motif chemokine 11 (CXCL11) and components of the Hedgehog signaling pathway were examined in HaCaT cells by MTT assay, flow cytometric analysis, ELISA and gene chip analysis. The data showed that rhPTH (1-34) significantly inhibited keratinocyte proliferation at concentrations >8×10−7 mol/l. rhPTH (1-34) induced G1 phase arrest of the cell cycle in the keratinocytes. The secretion of CXCL11 in tumor necrosis factor (TNF)-α-induced keratinocytes was downregulated by rhPTH (1-34) in a dose-dependent manner, compared with that in keratinocytes treated with TNF-α alone. It was also found that rhPTH (1-34) inhibited the expression of CXCL11 in the HaCaT cells. rhPTH (1-34) also affected the Hedgehog signaling pathway specifically by regulating the expression of associated genes. In conclusion, these data suggested that rhPTH (1-34) inhibited cell proliferation, and the secretion and expression of CXCL11 in HaCaTs. rhPTH (1-34) also altered the expression of associated genes in the Hedgehog pathway. Therefore, rhPTH (1-34) can be considered as a novel therapeutic agent for the treatment of psoriasis.

Background Photodynamic therapy (PDT) has been widely used in treatment for skin cancer. However, topical 5-aminolevulinic acid (ALA) in PDT demonstrates poor therapeutic effect due to its shallow penetration. And intralesional ALA-PDT can bring great pain. The purpose of this study was to evaluate the efficacy of PDT with needle-free injection of ALA in the treatment of nonmalignant skin tumors. Methods 54 non-melanocytic malignant lesions of 54 subjects were treated with needle-free injection of 20% 5-ALA under occlusion for 1.5 hours, and irradiated with light dose of 100 J/cm2 at 100 mW for 20 minutes. Evaluation of treatment efficacy was conducted at 2 week after treatment. Results 44 cases showed complete response with six cycles of PDT, three cases with seven cycles, and three cases with nine cycles. The remaining four cases failed to show complete response even with nine cycle of PDT. No case was reported to have recurrence in 6 months posttreatment. Only four cases experienced disease recurrence in 1 year posttreatment. Conclusions The treatment with PDT using needle-free injection of 5-ALA appears to be effective and well tolerated with milder therapeutic pain and low recurrence rate. It can be proposed as an effective treatment alternative for non-melanoma skin cancer.

Background Malignant acanthosis nigricans (MAN), characterized by the presence of a hyperpigmented, velvety cutaneous thickening, is recognized as a cutaneous sign of internal malignancy. Few MAN has been reported in the Asian race ever before. Case presentation Here, we report a rare case of MAN with severe mucosa and soles and extraordinary facial involvement in the Asian race. A 74-year-old man presented with hyperkeratotic eruption for 7 months. Physical examination revealed hyperkeratotic plaques on the face, dorsal skin of fingers and heels, and papillomatosis of buccal mucosa. Biopsy findings from skin lesion revealed hyperkeratosis, papillomatosis, and hyperpigmentation of the basal layer. The endoscopic ultrasound with biopsy of the gastric tissue revealed gastric cardia tubular adenocarcinoma. The patient was diagnosed with MAN associated with gastric adenocarcinoma, immediately following tumor resection and lymphadenectomy. A slight improvement was seen in the skin condition but died of cancer cachexia 3 months later. Conclusions We report our typical patient to highlight the importance of MAN, which was an early clue to the discovery of gastric adenocarcinoma.

YAP is a critical protein in cancer development and can induce transformative phenotypes in mammary epithelial cells. Previous studies have provided evidence that YAP can contribute to the metastatic behavior of melanoma, since specific knockdown of YAP leads to reduced metastatic and invasive capacity in vitro. However, the mechanism by which YAP regulates the function of melanoma is unknown. Here, we identified that YAP has a positive impact on the expression of LRP1, which also plays critical roles in cancer. Mechanically, knockdown of YAP resulted in a significant down-regulation of LRP1 at both the protein and mRNA levels. Tissue microarray analysis (TMA) also showed a positive correlation between YAP and LRP1 expression. In addition, reduction of YAP-impaired pro-carcinogenic phenotypes could be partially reversed by simultaneous overexpression of LRP1, suggesting that LRP1 is functionally important in YAP-induced melanoma tumorigenesis. Furthermore, we found that LRP1 was regulated by YAP through a transcription- and promoter-dependent mechanism. Taken together, our results suggest that YAP regulates LRP1 through stimulation of the LRP1 promoter and that LRP1 may be an important target for influencing YAP in melanoma.

Psoriasis is a chronic inflammatory disease of the skin which can occur at any age-group. Psoriasis in childhood is not uncommon and has genetic susceptibility but usually, an environmental trigger such as infection is thought to initiate the disease process. Pediatric psoriasis has profound effects on both physical and psychosocial health of the patient. Treatment of mild psoriasis can be done with topical therapies but those which do not respond to topical therapies can be treated with phototherapy and systemic therapies. The use of systemic therapies in childhood is mainly based on the published data, case series, expert opinion and the experience as there is the lack of controlled trials in the age group. Based on the experience retinoids are probably the second line drugs for the treatment of pediatric psoriasis which do not respond to topical therapies and phototherapy. Using acitretin in a low dose and with proper physical examinations and laboratory investigations will reduce the hazard of potential serious adverse events. This article gives the review of the use of acitretin in pediatric psoriasis.

Psoriasis is a common, chronic inflammatory skin disease and cannot be cured. The treatment of moderate-to-severe plaque psoriasis has been revolutionized with the development of biologic agents for nearly 20 years. Current studies show that interleukin-23 and interleukin-17 play remarkable roles in the pathogenesis of psoriasis. Interleukin-23 can sustain the differentiation and maintenance of T helper-17 lineage. Interleukin-17 can recruit and stimulate many cells, which play important parts in psoriasis through interacting with the interleukin-17 receptor. Several biologic agents targeting interleukin-23, interleukin-17, or their receptors are now in different stages: some are approved or clinical trials are in progress. Ustekinumab targets interleukin-23/interleukin-12p40; risankizumab, guselkumab, and tildrakizumab target interleukin-23p19; secukinumab and ixekizumab target interleukin-17A; and brodalumab targets the interleukin-17 receptors. All of these agents have good efficacy in treating moderate-to-severe psoriasis.

Background Psoriasis is a high-incident T-cell-mediated autoimmune disease mainly affecting the skin. Interleukin (IL)-27 is a novel member of the IL-6/IL-12 cytokine family, which plays a versatile role in the differentiation and function of distinct T cell subsets. Previous studies uncovered that IL-27 promoted the onset of psoriasis through enhancing the differentiation of T helper (Th) 1 cells. However, the role of IL-27 in other psoriasis-related Th lineages, especially Th17 cells, remains elusive. Objects The study aimed to investigate the role of IL-27 in the progression of psoriasis and its underlying mechanisms, particularly its influence on Th1 and Th17. Methods IL-27 and IL-27 receptor α (IL-27Rα) expressions in normal and lesional skin were determined by immunohistochemistry and western blot analysis. Serum levels of IL-27 and IL-10 were measured by ELISA. Expression levels of IL-27 and IL-27 receptor (IL-27R) mRNA in the skin tissue and peripheral blood mononuclear cells (PBMC) were assessed by quantitative polymerase chain reaction (PCR) analysis. To explore the function of IL-27 in vivo , we used imiquimod (IMQ)-induced psoriasis mouse model. We treated mice with IL-27 or its antagonist, evaluated disease severity and detected the cytokine secretion from splenic CD4+ T cells by flow cytometric analysis and the expression levels of IL-17 and IFN-γ in serum and skin lesion. Results The expression levels of IL-27 and IL-27Rα were significantly reduced in the moderate-to-severe psoriatic lesions, along with a consistent decrease in serum IL-27 levels, compared with those of healthy control subjects. Moreover, subcutaneous administration of IL-27 recombinant protein lessened severity of IMQ-induced psoriasis-like cutaneous lesions, whereas IL-27p28 antagonist exaggerated the disease severity. Further analysis revealed that IL-27 significantly repressed IL-17 secretion from CD4+ T lymphocytes. Also administration of IL-27 decreased IL-17A level while IL-27p28 antagonist increased IL-17A level in serum and psoriasis-like lesion in the IMQ-treated mice. Conclusion Our results suggest that IL-27 might predominantly play a protective role in the pathogenesis of psoriasis through abrogating Th17 differentiation. The potential therapeutic benefit of harnessing IL-27 in treating psoriasis awaits future investigation.

Background: Reactive perforating collagenosis (RPC) is a rare form of transepithelial elimination, in which altered collagen is extruded through the epidermis. There are 2 types of RPC, acquired RPC (ARPC) and inherited RPC, while the latter is extremely rare. Here we report on 1 case of ARPC. Methods: A 73-year-old female was presented with strongly itchy papules over her back and lower limbs for 3 months. She denied the history of oozing or vesiculation. A cutaneous examination showed diffusely distributed multiple well-defined keratotic papules, 4 to 10 mm in diameter, on the bilateral lower limbs and back as well as a few papules on her chest and forearm. Scratching scars were over the resolved lesions while Koebner phenomenon was negative. The patient had a history of type 2 diabetes for 15 years. Laboratory examinations showed elevated blood glucose level. Skin lesion biopsy showed a well-circumscribed area of necrosis filled with a keratotic plug. Parakeratotic cells and lymphocytic infiltration could be seen in the necrosed area. In dermis, sparse fiber bundles were seen perforating the epidermis. These degenerated fiber bundles were notarized as collagen fiber by elastic fiber stain, suggesting a diagnosis of RPC. Results: Then a diagnosis of ARPC was made according to the onset age and the history of diabetes mellitus. She was treated with topical application of corticosteroids twice a day and oral antihistamine once a day along with compound glycyrrhizin tablets 3 times a day. And the blood glucose was controlled in a satisfying range. Two months later, a significant improvement was seen in this patient. Conclusion: Since there is no efficient therapy to RPC, moreover, ARPC is considered to be associated with some systemic diseases, the management of the coexisting disease is quite crucial. The patient in this case received a substantial improvement due to the control of blood glucose and application of compound glycyrrhizin tablets.

Immunosenescence is a result of progressive decline in immune system function with advancing age. Epidermal Langerhans cells (LCs), belonging to the dendritic cell (DC) family, act as sentinels to play key roles in the skin immune responses. However, it has not been fully elucidated how aging affects development and function of LCs. Here, we systemically analyzed LC development and function during the aging process in C57BL/6J mice, and performed global microRNA (miRNA) gene expression profiles in aged and young LCs. We found that the frequency and maturation of epidermal LCs were significantly reduced in aged mice starting at 12 months of age, while the Langerin expression and ability to phagocytose Dextran in aged LCs were increased compared to LCs from < 6 month old mice. The migration of LCs to draining lymph nodes was comparable between aged and young mice. Functionally, aged LCs were impaired in their capacity to induce OVA-specific CD4+ and CD8+ T cell proliferation. Furthermore, the expression of miRNAs in aged epidermal LCs showed a distinct profile compared to young LCs. Most interestingly, aging-regulated miRNAs potentially target TGF-β-dependent and non- TGF-β-dependent signal pathways related to LCs. Overall, our data suggests that aging affects LCs development and function, and that age-regulated miRNAs may contribute to the LC developmental and functional changes in aging.

TO THE EDITOR Epidermal Langerhans cells (LCs) are professional antigen-presenting dendritic cells (DCs) that reside in the epidermis and form the first immunological barrier to the external environment (Romani et al., 2010). Although considerable progress has been made in identifying the developmental requirement of LCs, the mechanisms that regulate LC development and homeostasis are still not fully elucidated. TGF-β1 is one of key regulators to control LC development and homeostasis. LCs are absent in mice that lack TGF-β1, owing to a failure in LC differentiation, survival or both (Borkowski et al., 1996; Kaplan et al., 2007; Zahner et al., 2011). This finding is further supported by the dependence of LCs development on other TGFβ1-related molecules, including inhibitor of DNA binding 2 (ID2), a TGFβ1-induced inhibitor of helix–loop–helix transcription factors (Hacker et al., 2003), and Runx3, specifically expressed by mature DCs and mediates their response to TGFβ1 (Fainaru et al., 2004). Furthermore, TGF-β1 is also required to maintain the pool of immature LCs in the epidermis (Kel et al., 2010). Although TGF-β1 is expressed by both keratinocytes and LCs, an autocrine source of TGF-β1 from LCs is required for LC development (Kaplan et al., 2007). Taken together, TGF-β1 is essential for the ontogeny, homeostasis, and function of epidermal LCs. However, the intracellular signaling pathway of TGF-β1 in epidermal LCs remains elusive. In a well-defined classical TGF-β linear signaling pathway, once activated, TGF-β1 signals through its two cell surface receptors, TGF-β receptor 1 (TβR1) and TGF-β receptor 2 (TβR2), leading to Smad-mediated transcriptional regulation. There are eight Smads: Smad1 to Smad8. Smad2 and Smad3 are activated through carboxy-terminal phosphorylation by TGFβ1. These receptor-activated Smads (R-Smads) are released from the receptor complex to form a heterotrimeric complex with a common Smad4, and translocate into the nucleus to regulate the transcription of target genes (Derynck and Zhang, 2003; Tsukazaki et al., 1998). In addition, TGF-β1 also can activate other signaling cascades, including MAPK pathways (Itoh et al., 2000; Massague, 2000; Moustakas et al., 2001). Unlike mice with the conventional disruptions of Smad2 and Smad4 that are lethal, mice with Smad3 deficiency are viable and can survive. However, Smad3 knockout (KO) mice develop progressive diseases, including leucocytosis and massive inflammation. The loss of Smad3 results in multiple cell defects, including T cells, neutriphils and macrophage (Werner et al., 2000; Yang et al., 1999). Here we used Smad3 KO mice (Datto et al., 1999) to directly test if TGFβ/Smad3 signaling pathway is involved in the ontogeny and homeostasis of epidermal LCs. During LC early development, a single wave of LC precursors recruited in the epidermis around embryonic day 18, which subsequently differentiate into LCs after birth, and LCs then undergo a massive burst proliferation during the first week of life to form a typical LC network (Chorro et al., 2009). Given that TGF-β signals are required for ontogeny and maintaining of LCs in the epidermis, we first assessed if Smad3 is required for LC homeostasis in vivo. Epidermal cell suspensions prepared from ears and dorsal skin of Smad3KO mice and WT littermates, on day 0, 1, 3, 8 after birth, as well as at 3 and 5-week old, were stained with anti-Langerin and anti-MHC-II antibodies. As shown in Figure 1 a & b, we did observe a 3–4-fold expansion of LCs from 0.78 ± 0.11% on day 0 to 2.72 ± 0.14% on day 3 in WT mice. Langerin expression was undetectable in MHCII+ LCs in the epidermis on day 0 and 1, but upregulated Langerin expression was detected in about 70%–80% LCs by day 3, which is consistent with recent report (Chorro et al., 2009; Kel et al., 2010). However, there were no significant differences on the rations of epidermal LCs between Smad3 KO and WT mice at any time points by flow cytometry (Figure 1a & b) and immunohistological staining at day 0 after born and 5 weeks old (Figure 1c & d). Thus, Smad3 is not required in the TGF-β signal pathway for oncogeny and homeostasis of epidermis LCs. Figure 1 Smad3 is not required for ontogeny and homeostasis of epidermis LCs. (a) and (b) Epidermal suspensions prepared from ears and trunk skin of Smad3 KO and WT littermates on day 0, 1, 3, 8 after birth, as well as at 3 and 5 weeks old, were stained with anti-Langerin ... Upon activation by various stimuli, immature LCs residing in epidermis collect antigen and increase their MHC II and costimulatory molecules, including CD80 and CD86, and then migrate to T cells areas of draining lymph nodes, leading to immune responses (Romani et al., 2010). However, loss of TβR1 in LCs makes LC spontaneous maturation, suggesting the TGF-β signal as an essential pathway to control the immature state of LCs (Kel et al., 2010). We next tested if TGF-β/Smad3 signaling pathway is required for maintaining the immature state of epidermal LCs. As shown in Figure 2a, the frequencies of CD80+ LCs and CD86+LCs were comparable between Smad3 KO and WT mice. Furthermore, the expression levels of MHCII, CD80 and CD86 on LCs, represented by mean fluorescence intensity (MFI), were not changed (Figure 2b). LC maturation in Smad3 KO mice were further evaluated after in vitro epidermal culture. As shown in Figure 2c, after 60h culture, both the percentages of CD86- and CD80-positive LCs and MHCIIhigh LCs as well as the relative CD80, CD86, and MHCII expression levels on LCs (Figure 2d) were significantly increased in Smad3KO and WT mice compared to unstimulation condition (Figure 2a & b), but there was no significant difference between Smad3 KO and WT mice (P > 0.05). Thus, the lack of Smad3 signaling does not affect the immature state of LCs as well as LC maturation. Figure 2 Smad3 is not an essential factor to control epidermis LC maturation and LC uptaking-antigen ability. (a) and (b) Epidermal suspensions freshly isolated from ears and trunk skin of Smad3 KO and WT littermates at 5 weeks old, were stained with anti-Langerin, ... Due to their physical location, LCs acquire and process antigens. To evaluate the role of Smad3 in antigen phagocytic function of LCs, freshly isolated epidermal cells from KO and WT mice were incubated at 37°C or 4°C (as control) with FITC-Dextran for 45 minutes and then stained with anti-mouse MHC-II and CD45.2 antibodies. As shown in Figure 2e, the phagocytic capacity of LCs in Smad3 KO mice had no significant difference (P > 0.05) compared to the WT LCs, based on the ratio of FITC-positive LCs (Figure 2e) or MFI expression levels (Figure 2f). Thus, lack of Smad3 signal pathway does not affect LC phagocytosis. In summary, lack of Smad3 surprisingly does not significantly interrupt the development and immature state of epidermal LCs, and Smad3-deficient LCs have normal maturation and phagocytosis. Our data suggest that Smad3 is not required in the TGF-β signal pathway for ontogeny, homeostasis, and function of epidermal LCs. Recent report indicated that Smad2 and Smad3 were redundantly essential for TGF-β–mediated induction of Foxp3-expressing regulatory T cells and suppression of IFN-γ production in CD4+ T cells (Takimoto et al., 2010). This raises the possibility that Smad2/Smad3 redundancy may also exist in TGF-β/Smads pathways in LCs. In addition, non-TGF-β/Smads pathways may also regulate LC ontogeny and homeostasis (Figure 2g). Further investigations are warranted to clarify the TGF-β signaling pathways through which TGF-β controls LC ontogeny and homeostasis.

Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model. IL-25 injection induced skin inflammation, whereas germline or keratinocyte-specific deletion of IL-25 caused resistance to IMQ-induced psoriasis. Via IL-17RB expression in keratinocytes, IL-25 stimulated the proliferation of keratinocytes and induced the production of inflammatory cytokines and chemokines, via activation of the STAT3 transcription factor. Thus, our data demonstrate that an IL-17-induced autoregulatory circuit in keratinocytes is mediated by IL-25 and suggest that this circuit could be targeted in the treatment of psoriasis patients.

Background Naringin is a bioflavonoid and has free radical scavenging and anti-inflammatory properties. Methods We examined the effects of naringin on skin after ultraviolet radiation B (UVB) irradiation and the signal pathways by in vitro and in vivo assay. Results HaCaT cells pretreated with naringin significantly inhibited UVB induced-cell apoptosis and production of intracellular reactive oxygen species (ROS). The expressions of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2) in HaCaT cells pretreated with naringin were decreased compared with the only UVB group. Also, the activation of p38 induced by UVB in HaCaT cells was reversed by naringin treatments. The inhibition function of naringin on p38 activity was more obvious than JNK. In vivo, topical treatments with naringin prevented the increase of epidermal thickness, IL-6 production, cell apoptosis and the overexpression of COX-2 in BALB/c mice skin irradiated with UVB. Naringin treatment also markedly blocked the activation of p38 in response to UVB stimulation in the mouse skin. Conclusion Naringin can effectively protect against UVB-induced keratinocyte apoptosis and skin damage by inhibiting ROS production, COX-2 overexpression and strong inflammation reactions. It seemed that naringin played its role against UVB-induced skin damage through inhibition of mitogen-activated protein kinase (MAPK)/p38 activation.

Activation of the transcription factor NF-κB by multiple genotoxic stimuli modulates cancer cell survival. This response is mediated by a conserved pathway involving the nuclear ATM kinase and cytoplasmic IκB kinase (IKK); however, the molecular link between them remains incompletely understood. Here we show that ATM activates the IKK kinase TAK1 in a manner dependent on IKKγ/NEMO and ELKS (a protein rich in glutamate, leucine, lysine, and serine). K63-linked polyubiquitination of ELKS, dependent on the ubiquitin ligase XIAP and the conjugating enzyme UBC13, allows ELKS association with TAK1 via its ubiquitin-binding subunits TAB2/3. Although NEMO mutants defective in ubiquitin binding permit ATM-dependent TAK1 activation, they block NEMO association with ELKS and IKK activation. Thus, ATM- and NEMO-dependent ubiquitination of ELKS leads to the ubiquitin-dependent assembly of TAK1/TAB2/3 and NEMO/IKK complexes, resulting in IKK and NF-κB activation following genotoxic stimuli.