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Background: Non-scarring alopecia is typically represented by two main types: alopecia areata (AA) and androgenetic alopecia (AGA). While previous observational studies have indicated a link between non-scarring alopecia and hypothyroidism, the precise causal relationship remains uncertain. To determine the potential links between non-scarring alopecia and hypothyroidism, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. Methods: We used independent genetic instruments from the FinnGen consortium for AA (682 cases, 361,140 controls) and AGA (195 cases, 201,019 controls) to investigate the association with hypothyroidism in the UK Biobank study (22,687 cases, 440,246 controls). The primary analysis was performed using the inverse variance-weighted method. Complementary approaches were employed to evaluate the pleiotropy and heterogeneity. Results: Genetically predicted AA exhibited a positive causal effect on hypothyroidism (odds ratio [OR], 1.0017; 95% confidence interval [CI], 1.0004-1.0029; P = 0.0101). Additionally, hypothyroidism was found to be strongly correlated with an increase in the risk of AA (OR, 45.6839; 95% CI, 1.8446-1131.4271, P = 0.0196). However, no causal relationship was demonstrated between AGA and hypothyroidism. A sensitivity analysis validated the integrity of these causal relationships. Conclusion: This MR study supports a bidirectional causal link between AA and hypothyroidism. Nevertheless, additional research is needed to gain a more thorough comprehension of the causal relationship between non-scarring alopecia and hypothyroidism.
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Alopecia Areata , Hipotiroidismo , Humanos , Análisis de la Aleatorización Mendeliana , Hipotiroidismo/complicaciones , Hipotiroidismo/genética , Oportunidad RelativaRESUMEN
Bullous pemphigoid (BP) is the most prevalent autoimmune vesiculobullous skin illness that tends to affect the elderly. Growing evidence has hinted a correlation between BP and neurological diseases. However, existing observational studies contained inconsistent results, and the causality and direction of their relationship remain poorly understood. To assess the causal relationship between BP and neurological disorders, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and stroke. A bidirectional two-sample Mendelian randomization (MR) adopted independent top genetic variants as instruments from the largest accessible genome-wide association studies (GWASs), with BP (n = 218 348), PD (n = 482 730), AD (n = 63 926), stroke (n = 446 696), and MS (n = 115 803). Inverse variance weighted (IVW), MR-Egger, weighted mode methods, weighted median, and simple mode were performed to explore the causal association. Multiple sensitivity analyses, MR-Pleiotropy Residual Sum and Outlier (PRESSO) was used to evaluate horizontal pleiotropy and remove outliers. With close-to-zero effect estimates, no causal impact of BP on the risk of the four neurological diseases was discovered. However, we found that MS was positively correlated with higher odds of BP (OR = 1.220, 95% CI: 1.058-1.408, p = 0.006), while no causal associations were observed between PD (OR = 0.821, 95% CI: 0.616-1.093, p = 0.176), AD (OR = 1.066, 95% CI: 0.873-1.358, p = 0.603), stroke (OR = 0.911, 95% CI: 0.485-1.713, p = 0.773) and odds of BP. In summary, no causal impact of BP on the risk of PD, AD, MS and stroke was detected in our MR analysis. However, reverse MR analysis identified that only MS was positively correlated with higher odds of BP, but not PD, AD and stroke.
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Enfermedades del Sistema Nervioso , Enfermedad de Parkinson , Penfigoide Ampolloso , Accidente Cerebrovascular , Anciano , Humanos , Penfigoide Ampolloso/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedades del Sistema Nervioso/genética , Enfermedad de Parkinson/genéticaRESUMEN
BACKGROUND: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. OBJECTIVES: We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms. METHODS: Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated. RESULTS: Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1ß secretion through modulation of ER stress via the PERK-eIF2α-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. CONCLUSIONS: In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.
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Dermatitis , Proteínas Filagrina , Animales , Humanos , Ratones , Acetona/metabolismo , Acetona/farmacología , Dermatitis/metabolismo , Epidermis/metabolismo , Inflamasomas/metabolismo , Inflamación , Queratinocitos/metabolismo , Proteínas NLR/metabolismoRESUMEN
Psoriasis is a chronic, refractory inflammatory skin disease, with a high prevalence of psychiatric comorbidities, including depression, anxiety, and even suicidality, which may in turn initiate or exacerbate skin inflammation. However, the causal relationships between these comorbidities remain unclear. To investigate the cause-effect relationships between psoriasis and mental disorders including depression, anxiety, and suicidality, we conducted a bidirectional two-sample Mendelian randomization (MR) study utilizing summary statistics from the most comprehensive genome-wide association studies of psoriasis (n = 306 123), broad depression (n = 500 199), major depressive disorder (n = 173 005), anxiety (n = 17 310), and suicide attempts (n = 50 264). Using the random-effects inverse-variance weighted method as primary method, the forward MR analyses indicated that psoriasis was significantly associated with higher odds of broad depression (odds ratio [OR] 1.030, 95% confidence interval [CI] 1.010-1.051, P = 0.003) and suggestively associated with an increased risk of major depressive disorder (OR 1.054, 95% CI 1.002-1.109, P = 0.040), but not with the risk of anxiety (P = 0.160) or suicide attempts (P = 0.648). In reverse MR analyses, significant causal impact of broad depression (OR 1.363, 95% CI 1.103-1.684, P = 0.004) and major depressive disorder (OR 1.890, 95% CI 1.285-2.781, P = 0.001), but not anxiety (P = 0.787) and suicide attempts (P = 0.961) on psoriasis risk was observed. In addition, the results of primary analysis are consistent across sensitivity analyses, albeit the MR-Egger regression model produced wide CIs and negative results in several analyses. In conclusion, this MR study indicates a bidirectional causal relationship between psoriasis and depression that was previously unrecognized, which highlights the significance of screening for depression in psoriasis patients and initiating appropriate interventions. Further studies are required to elucidate the pathophysiology of the bidirectional causal relationship between these two conditions.
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Trastorno Depresivo Mayor , Dermatitis , Psoriasis , Suicidio , Humanos , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Depresión/epidemiología , Depresión/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Ansiedad/epidemiología , Psoriasis/epidemiología , Psoriasis/genéticaRESUMEN
Neutrophils have a pathogenic function in inflammation via releasing pro-inflammatory mediators or neutrophil extracellular traps (NETs). However, their heterogeneity and pro-inflammatory mechanisms remain unclear. Here, we demonstrate that CXCR4hi neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4lo neutrophils, CXCR4hi neutrophils have enhanced NETs formation, phagocytic function, neutrophil degranulation, and overexpression of pro-inflammatory cytokines and chemokines in vitro. This is accompanied by a metabolic shift in CXCR4hi neutrophils toward glycolysis and lactate release, thereby promoting vascular permeability and remodeling. CXCR4 expression in neutrophils is dependent on CREB1, a transcription factor activated by TNF and CXCL12, and regulated by de novo synthesis. In vivo, CXCR4hi neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4hi neutrophils through CXCR4 or CXCL12 inhibition leads to suppression of immune responses. In this work, our study identifies CREB1 as a critical regulator of CXCR4hi neutrophil development and characterizes the contribution of CXCR4hi neutrophils to vascular remodeling and inflammatory responses in skin.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Dermatitis , Psoriasis , Animales , Humanos , Ratones , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Modelos Animales de Enfermedad , Inflamación , Neutrófilos , Psoriasis/genética , Receptores CXCR4/genética , PielRESUMEN
Dysfunction of vascular endothelial cells (ECs) facilitates imbalanced immune responses and tissue hyperinflammation. However, the heterogeneous functions of skin ECs and their underlying mechanism in dermatoses remain to be determined. Here, focusing on the pathogenic role of skin ECs in psoriasis, we characterized the molecular and functional heterogeneity of skin ECs from healthy individuals and psoriasis patients at the single-cell level. We found that endothelial glycocalyx destruction, a major feature of EC dysfunction in psoriasis, was a driving force during the process of T cell extravasation. Interestingly, we identified a skin EC subset, IGFBP7hi ECs, in psoriasis. This subset actively responded to psoriatic-related cytokine signaling, secreted IGFBP7, damaged the endothelial glycocalyx, exposed the adhesion molecules underneath, and prepared the endothelium for immune-cell adhesion and transmigration, thus aggravating skin inflammation. More importantly, we provided evidence in a psoriasis-like mouse model that anti-IGFBP7 treatment showed promising therapeutic effects for restoring the endothelial glycocalyx and alleviating skin inflammation. Taken together, our results depict the distinct functions of EC clusters in healthy and psoriatic skin, identify IGFBP7hi ECs as an active subset modulating vascular function and cutaneous inflammation, and indicate that targeting IGFBP7 is a potential therapeutic strategy in psoriasis.
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Glicocálix , Psoriasis , Ratones , Animales , Glicocálix/metabolismo , Glicocálix/patología , Células Endoteliales/metabolismo , Psoriasis/patología , Linfocitos T , Inflamación/metabolismoRESUMEN
Cutaneous dendritic cells (DCs) have been implicated in the pathogenesis of atopic dermatitis (AD). However, the specific role of different subsets of DCs has not been well defined. This study aimed to investigate the contributions of Langerhans cells (LCs), resident dermal Langerin+ DCs (r-Langerin+ dDCs), and newly infiltrated inflammatory dermal Langerin+ DCs (i-Langerin+ dDCs) in an AD mouse model induced by the topical application of MC903. The result showed that depletion of i-Langerin+ dDCs in DTR mice after multiple diphtheria toxin (DT) injection significantly reduced thymic stromal lymphopoietin (TSLP) production in lesions and skin inflammation alleviation. However, depletion of LCs or r-Langerin+ dDCs didn't resulted in significant changes in skin inflammation of DTA or single DT injection-treated DTR mice compared with the wild-type (WT) mice. DT-treated DTR-WT chimeric mice with the depletion of bone marrow (BM)-derived i-Langerin+ dDCs resulted in markedly decreased skin inflammation than controls, while PBS-treated chimeric mice (DTR-WT) with only the depletion of r-Langerin+ dDCs showed inflammation comparable to that in WT mice. Furthermore, TSLP contributed to the upregulation of Langerin expression in BM-derived DCs and promoted the maturation of Langerin+ DCs. In summary, the present study demonstrated that the newly infiltrated inflammatory dermal Langerin+ DCs were essential for AD development and local TSLP production, and TSLP further promoted the production of BM-derived i-Langerin+ dDCs, which might maintain AD inflammation.
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Dermatitis Atópica , Lectinas de Unión a Manosa , Ratones , Animales , Lectinas de Unión a Manosa/metabolismo , Dermatitis Atópica/metabolismo , Lectinas Tipo C/metabolismo , Células Dendríticas/metabolismo , Antígenos de Superficie/metabolismo , Ratones Endogámicos C57BL , Inflamación/metabolismo , Modelos Animales de EnfermedadRESUMEN
Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin inflammation, or vice versa, remains poorly understood. Here, we report that the levels of sebum and its microbial metabolite, propionate, were lower on the skin surface of AD patients compared with those of healthy individuals. Topical propionate application attenuated skin inflammation in mice with MC903-induced AD-like dermatitis by inhibiting IL-33 production in keratinocytes, an effect that was mediated through inhibition of HDAC and regulation of the AhR signaling pathway. Mice lacking sebum spontaneously developed AD-like dermatitis, which was improved by topical propionate application. A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionate application in AD patients. In summary, we have uncovered that the dysregulated sebum-microbial metabolite-IL-33 axis might play an initiating role in AD-related skin inflammation, thereby highlighting novel therapeutic strategies for the treatment of AD.
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Dermatitis Atópica , Interleucina-33/biosíntesis , Animales , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Inflamación/patología , Interleucina-33/metabolismo , Queratinocitos/metabolismo , Ratones , Propionatos/metabolismo , Propionatos/farmacología , Propionatos/uso terapéutico , Sebo/metabolismo , Piel/patologíaRESUMEN
Disseminated facial verruca plana is a chronic disorder that causes significant psychological distress. However, safe and effective treatment is lacking. This study aimed to explore the efficacy and safety of 35% glycolic acid (GA) for the treatment of disseminated facial verruca plana. A split-face clinical trial was conducted to explore the efficacy and safety of using chemical peeling with 35% GA for the treatment of disseminated facial verruca plana. One side of the face was applied with 35% GA once every fortnight for a total of three times. Adapalene gel was applied every night to the other side of the face as the control. The clearance rate of lesions was evaluated at different time points. Between June 2020 and December 2020, 30 patients with disseminated verruca plana who visited the Dermatology Hospital of Southern Medical University were enrolled. After three chemical peelings with 35% GA that was applied at 2-week intervals, 15 (50%) patients achieved >70% lesion reduction. The same effective rate in the adapalene gel-treated side of the face was documented in eight patients. Subgroup analysis showed a higher clearance rate in patients with a shorter disease duration. Moreover, concurrent improvements in facial roughness were observed in the 35% GA-treated group. Adverse effects including mild erythema and desquamation were observed during chemical peeling with 35% GA. In conclusion, chemical peeling with 35% GA could be a safe and effective option for treating disseminated facial verruca plana, especially for those who desire skin improvement.
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Quimioexfoliación , Verrugas , Adapaleno , Quimioexfoliación/efectos adversos , Glicolatos/efectos adversos , Humanos , Resultado del Tratamiento , Verrugas/tratamiento farmacológicoAsunto(s)
Técnicas Cosméticas , Envejecimiento de la Piel , Humanos , Rejuvenecimiento , Cara , Ondas de RadioRESUMEN
Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity response to skin contact allergens in which keratinocytes are critical in the initiation of early responses. Keratin 17 (K17) is a cytoskeletal protein inducible under stressful conditions and regulates multiple cellular processes, especially in skin inflammatory diseases; however, knowledge regarding its contribution to ACD pathogenesis remains ill defined. In the present study, we clarified the proinflammatory role of K17 in an oxazolone (OXA)-induced contact hypersensitivity (CHS) murine model and identified the underlying molecular mechanisms. Our results showed that K17 was highly expressed in the lesional skin of ACD patients and OXA-induced CHS mice. Mice lacking K17 exhibited alleviated OXA-induced skin inflammation, including milder ear swelling, a reduced frequency of T cell infiltration, and decreased inflammatory cytokine levels. In vitro, K17 stimulated and activated human keratinocytes to produce plenty of proinflammatory mediators, especially the chemokine CCL20, and promoted keratinocyte-mediated T cell trafficking. The neutralization of CCL20 with a CCL20-neutralizing monoclonal antibody significantly alleviated OXA-induced skin inflammation in vivo. Moreover, K17 could translocate into the nucleus of activated keratinocytes through a process dependent on the nuclear-localization signal (NLS) and nuclear-export signal (NES) sequences, thus facilitating the activation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3), further promoting the production of CCL20 and T cell trafficking to the lesional skin. Taken together, these results highlight the novel roles of K17 in driving allergen-induced skin inflammation and suggest targeting K17 as a potential strategy for ACD.
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Quimiocinas CC/metabolismo , Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/metabolismo , Queratina-17/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Biomarcadores , Quimiocinas CC/genética , Citocinas/metabolismo , Dermatitis Alérgica por Contacto/diagnóstico , Susceptibilidad a Enfermedades , Humanos , Mediadores de Inflamación , RatonesRESUMEN
OBJECTIVES: Ablative fractional CO2 laser (AFL) therapy is an effective intervention to induce dermal remodeling. AFL treatment of the skin triggers the recruitment of immune cells, with neutrophils dominating the early phase. However, the role of recruited neutrophils in AFL-induced microinjuries and their subsequent dermal remodeling capacity remains elusive. MATERIALS AND METHODS: A mouse model of AFL-induced dermal remodeling was established. RNA sequencing was used to identify the prominent features of AFL-treated tissues. Histological analysis, including H&E and Masson staining, ultrastructure observation by transmission microscopy, immunofluorescence, and quantitative real-time polymerase chain reaction were used for dermal remodeling analysis. Moreover, AFL-treated mice were intraperitoneally injected with anti-mouse Ly6G antibodies to deplete neutrophils. Neutrophil extracellular traps (NETs) were explored using immunofluorescence, transmission microscopy, and in vitro coculture experiments. RESULTS: Dermal remodeling, characterized by an increased number of CD31-positve vessels and elevated messenger RNA (mRNA) expression of genes encoding transforming growth factor-ß (TGF-ß), collagen I, and collagen III, was observed at 15 days after AFL treatment. In the AFL-induced inflammation phase, RNA sequencing identified neutrophil chemotaxis, and degranulation genes were significantly enriched. Histology and immunofluorescence staining of human and mouse tissues harvested at Day 1 after AFL treatment revealed significant neutrophil infiltration surrounding thermal-induced microinjuries. Neutrophil depletion decreased the expression of stress-related genes such as S100A8 and S100A9 in the early phase following AFL treatment. Importantly, neutrophil depletion enhanced dermal remodeling at Day 15, as reflected by enrichment of the extracellular matrix and collagen biosynthesis genes based on RNA sequencing. Moreover, increased collagen I, collagen III, and TGF-ß mRNA expression, increased cell proliferation, and vascularity were observed. Interestingly, NETs, which could be induced by AFL-treated fibroblasts in vitro, were identified in both human and mouse tissues on Day 1 after AFL treatment. CONCLUSIONS: AFL-treated human and mouse skin recruited a large number of neutrophils. The neutrophil surge impaired dermal remodeling in mice. The microenvironment and fibroblast functional modulation mediated by neutrophil degranulation and NET formation were determined to be the underlying mechanisms. Our results indicate that modification of infiltrated neutrophil activity might be a potential therapeutic target for AFL-induced dermal remodeling.
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Trampas Extracelulares , Láseres de Gas , Animales , Colágeno/metabolismo , Colágeno Tipo I , Trampas Extracelulares/metabolismo , Láseres de Gas/uso terapéutico , Ratones , Neutrófilos/metabolismo , ARN Mensajero/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Vascular endothelial cells (ECs) are increasingly recognized as active players in intercellular crosstalk more than passive linings of a conduit for nutrition delivery. Yet, their functional roles and heterogeneity in skin remain uncharacterized. We have used single-cell RNA sequencing (scRNA-seq) as a profiling strategy to investigate the tissue-specific features and intra-tissue heterogeneity in dermal ECs at single-cell level. Methods: Skin tissues collected from 10 donors were subjected to scRNA-seq. Human dermal EC atlas of over 23,000 single-cell transcriptomes was obtained and further analyzed. Arteriovenous markers discovered in scRNA-seq were validated in human skin samples via immunofluorescence. To illustrate tissue-specific characteristics of dermal ECs, ECs from other human tissues were extracted from previously reported data and compared with our transcriptomic data. Results: In comparison with ECs from other human tissues, dermal ECs possess unique characteristics in metabolism, cytokine signaling, chemotaxis, and cell adhesions. Within dermal ECs, 5 major subtypes were identified, which varied in molecular signatures and biological activities. Metabolic transcriptome analysis revealed a preference for oxidative phosphorylation in arteriole ECs when compared to capillary and venule ECs. Capillary ECs abundantly expressed HLA-II molecules, suggesting its immune-surveillance role. Post-capillary venule ECs, with high levels of adhesion molecules, were equipped with the capacity in immune cell arrest, adhesion, and infiltration. Conclusion: Our study provides a comprehensive characterization of EC features and heterogeneity in human dermis and sets the stage for future research in identifying disease-specific alterations of dermal ECs in various dermatoses.
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Dermis/citología , Células Endoteliales/metabolismo , Transcriptoma , Secuencia de Bases , Biomarcadores , Capilares/citología , Adhesión Celular , Dermis/irrigación sanguínea , Dermis/metabolismo , Expresión Génica , Humanos , Fenotipo , Análisis de la Célula Individual , Vénulas/citologíaRESUMEN
Excessive activation of CD4+ T cells and T helper type (Th) 17/Th1 cell differentiation are critical events in psoriasis pathogenesis, but the associated molecular mechanism is still unclear. Here, using quantitative proteomics analysis, we found that cyclin-dependent kinase 7 (CDK7) expression was markedly increased in CD4+ T cells from patients with psoriasis compared with healthy controls and was positively correlated with psoriasis severity. Meanwhile, genetic or pharmacological inhibition of CDK7 ameliorated the severity of psoriasis in the imiquimod-induced psoriasis-like mouse model and suppressed CD4+ T-cell activation as well as Th17/Th1 cell differentiation in vivo and in vitro. Furthermore, the CDK7 inhibitor also reduced the enhanced glycolysis of CD4+ T cells from patients with psoriasis. Proinflammatory cytokine IL-23 induced increased CDK7 expression in CD4+ T cells and activated the protein kinase B/mTOR/HIF-1α signaling pathway, enhancing glycolytic metabolism. Correspondingly, CDK7 inhibition significantly impaired IL-23-induced glycolysis via the protein kinase B/mTOR/HIF-1α pathway. In summary, this study shows that CDK7 promotes CD4+ T-cell activation and Th17/Th1 cell differentiation by regulating glycolysis, thus contributing to the pathogenesis of psoriasis. Targeting CDK7 might be a promising immunosuppressive strategy to control skin inflammation mediated by IL-23.
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Quinasas Ciclina-Dependientes/fisiología , Glucólisis , Psoriasis/inmunología , Células TH1/citología , Células Th17/citología , Animales , Diferenciación Celular , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Interleucina-23/fisiología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Psoriasis/etiología , Psoriasis/metabolismo , Células TH1/metabolismo , Células Th17/metabolismo , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
The epidermal barrier refers to the stratum corneum, the uppermost layer of the skin, and constitutes the first line of defense against invasion by potentially harmful pathogens, diminishes trans-epidermal water loss, and plays a crucial role in the maintenance of skin homeostasis. Keratin 17 (K17) is a type I epithelial keratin with multiple functions, including in skin inflammation, epithelial cell growth, protein synthesis, and tumorigenesis. However, the relationship between K17 and the skin barrier has yet to be systematically investigated. In this study, we found that acute disruption of the epidermal permeability barrier led to a rapid increase in epidermal K17 expression in vivo. Krt17 gene deficiency in mice resulted in decreased expression of lipid metabolism-related enzymes and antimicrobial peptides, while also delaying epidermal permeability barrier recovery after acute disruption. Adenovirus-mediated overexpression of K17 enhanced, whereas siRNA-mediated knockdown of Krt17 inhibited, the expression of fatty acid synthase (FASN) and that of the transcription factors SREBP-1 and PPARγ in vitro. We further confirmed that K17 can facilitate the nuclear transportation of SREBP-1 and PPARγ and promote lipid synthesis in keratinocytes. This study demonstrated that K17 contributes to the restoration of the epidermal permeability barrier via stabilizing lipid metabolism in keratinocytes.
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Neutrophil infiltration and papillary vessel dilation are hallmarks of the initiation phase of psoriatic lesions. However, how neutrophils aggravate psoriasis development during transendothelial migration and the interaction between neutrophils and cutaneous vascular endothelial cells are less well-understood. In this study, we reported that neutrophils and cutaneous vascular endothelial cells activated each other when neutrophils migrated through the cutaneous endothelial barrier. In addition, neutrophil infiltration into skin lesions caused vascular remodeling including cutaneous vasodilation and enhanced vascular permeability in vivo and in vitro. Microarray gene profile data showed that matrix metallopeptidase (MMP)-9 was overexpressed in psoriatic neutrophils, and zymography assay further validated the bioactivity of MMP-9 secreted by psoriatic neutrophils. Moreover, MMP-9 activated vascular endothelial cells through the extracellular signalâregulated kinase 1/2 and p38-MAPK signaling pathways, enhancing CD4+ T-cell transmigration in vitro. Correspondingly, an MMP-9 inhibitor significantly reduced cutaneous vasodilation, vascular permeability, and psoriatic symptoms in an imiquimod- or IL-23âinduced psoriasiform mouse model. Overall, our study demonstrates that neutrophil-derived MMP-9 induces cutaneous vasodilation and hyperpermeability by activating cutaneous vascular endothelial cells, thus facilitating psoriatic lesion development, which increases our knowledge on the role of neutrophils in the pathogenesis of psoriasis.
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Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Neutrófilos/inmunología , Psoriasis/inmunología , Animales , Biopsia , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/inmunología , Línea Celular , Quimiotaxis/inmunología , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/patología , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Femenino , Imiquimod/inmunología , Interleucina-23/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Ratones , Infiltración Neutrófila , Neutrófilos/metabolismo , Cultivo Primario de Células , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Proteínas Recombinantes/metabolismo , Piel/irrigación sanguínea , Piel/inmunología , Migración Transendotelial y Transepitelial/inmunología , Vasodilatación/inmunologíaRESUMEN
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced cutaneous reactions characterized by keratinocyte apoptosis. Exosomes are nanometer-sized membranous vesicles in body fluids. They contain functional proteins, mRNAs, and miRNAs, which induce immune dysfunction and influence disease progression. However, their roles and mechanisms in SJS/TEN remain unknown. Our results demonstrate that exosomes isolated from the plasma of patients with SJS/TEN were 30 to 200 nm in diameter and expressed CD9, CD63, CD81, and TSG101 exosome marker proteins. miR-375-3p was markedly up-regulated in 35 patients with SJS/TEN and correlated with clinical severity. Plasma exosomes were internalized by human primary keratinocytes and promoted keratinocyte apoptosis in vitro. Furthermore, miR-375-3p overexpression promoted intrinsic (mitochondria-dependent) apoptosis of human primary keratinocytes via down-regulation of the X-linked inhibitor of apoptosis protein (XIAP), a key apoptosis regulator in primary human keratinocytes. In sum, our study indicates that the circulating exosomal miR-375-3p enters keratinocytes, down-regulates XIAP, and induces keratinocyte apoptosis in patients with SJS/TEN.
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MicroARNs , Síndrome de Stevens-Johnson , Apoptosis , Humanos , Queratinocitos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Mitocondrias , Síndrome de Stevens-Johnson/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
BACKGROUND: Psoriasis is a common chronic inflammatory skin disease with 2% to 3% prevalence worldwide and a heavy social-psychological burden for patients and their families. As the exact pathogenesis of psoriasis is still unknown, the current treatment is far from satisfactory. Thus, there is an urgent need to find a more effective therapy for this disease. Keratin 17 (K17), a type I intermediate filament, is overexpressed in the psoriatic epidermis and plays a critical pathogenic role by stimulating T cells in psoriasis. Therefore, we hypothesized that inhibiting K17 may be a potential therapeutic approach for psoriasis. This study aimed to investigate the therapeutic effect of K17-specific small interfering RNA (siRNA) on mice with imiquimod (IMQ)-induced psoriasis-like dermatitis. METHODS: Eight-week-old female BALB/c mice were administered a 5% IMQ cream on both ears to produce psoriatic dermatitis. On day 3, K17 siRNA was mixed with an emulsion matrix and applied topically to the left ears of the mice after IMQ application every day for 7 days. The right ears of the mice were treated in parallel with negative control (NC) siRNA. Inflammation was evaluated by gross ear thickness, histopathology, the infiltration of inflammatory cells (CD3+ T cells and neutrophils) using immunofluorescence, and the expression of cytokine production using real-time quantitative polymerase chain reaction. The obtained data were statistically evaluated by unpaired t-tests and a one-way analysis of variance. RESULTS: The severity of IMQ-induced dermatitis on K17 siRNA-treated mice ears was significantly lower than that on NC siRNA-treated mice ears, as evidenced by the alleviated ear inflammation phenotype, including decreased ear thickness, infiltration of inflammatory cells (CD3+ T cells and neutrophils), and inflammatory cytokine/chemokine expression levels (interleukin 17 [IL-17], IL-22, IL-23, C-X-C motif chemokine ligand 1, and C-C motif chemokine ligand 20) (Pâ<â0.05 vs. the Blank or NC siRNA groups). Compared to the NC siRNA treatment, the K17 siRNA treatment resulted in increased K1 and K10 expression, which are characteristic of keratinocyte differentiation (vs. NC siRNA, K17 siRNA1 group: K1, tâ=â4.782, Pâ=â0.0050; K10, tâ=â3.365, Pâ=â0.0120; K17 siRNA2 group: K1, tâ=â4.104, Pâ=â0.0093; K10, tâ=â4.168, Pâ=â0.0042; siRNA Mix group: K1, tâ=â3.065, Pâ=â0.0221; K10, tâ=â10.83, Pâ<â0.0001), and decreased K16 expression, which is characteristic of keratinocyte proliferation (vs. NC siRNA, K17 siRNA1 group: tâ=â4.156, Pâ=â0.0043; K17 siRNA2 group: tâ=â2.834, Pâ=â0.0253; siRNA Mix group: tâ=â2.734, Pâ=â0.0250). CONCLUSIONS: Inhibition of K17 expression by its specific siRNA significantly alleviated inflammation in mice with IMQ-induced psoriasis-like dermatitis. Thus, gene therapy targeting K17 may be a potential treatment approach for psoriasis.