RESUMO
Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4-targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS-EMPD-1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H-score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4-targeted antibody-drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4-targeted ADC is promising as a therapeutic option for EMPD.
Assuntos
Neoplasias , Doença de Paget Extramamária , Humanos , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/patologia , Epiderme/metabolismo , Moléculas de Adesão CelularRESUMO
A 25-year-old female Carney complex patient with a PRKAR1A mutation who had undergone surgery to remove teratomas visited our dermatology department. She was suspected of having a malignant melanoma in a teratoma. On clinical examination, a black nodule was found within the cyst. On histopathological examination, the black lesion was composed of heavily pigmented round cells with vesicular nuclei and single prominent nucleoli. Additionally, there were large cells with irregularly shaped nuclei. Upon immunohistochemical examination, the large, irregularly shaped cells were positively stained with Melan A, HMB45, S-100 protein, SOX10, CD10 (focally), and BRAFV600E , but negatively stained with PRAME. Based on the histopathological features, we diagnosed the patient with pigmented epithelioid melanocytoma (PEM) in a teratoma of a Carney complex patient. This is the first case of PEM developing from a teratoma. Since PEM lesions may spread to regional lymph nodes, careful follow-up is necessary.
Assuntos
Complexo de Carney , Melanoma , Neoplasias Cutâneas , Teratoma , Feminino , Humanos , Adulto , Complexo de Carney/diagnóstico , Neoplasias Cutâneas/patologia , Mutação , Teratoma/diagnóstico , Antígenos de NeoplasiasRESUMO
Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)-nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR-NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Queratinócitos , Fator 2 Relacionado a NF-E2 , Inibidores da Fosfodiesterase 4 , Receptores de Hidrocarboneto Arílico , Transdução de Sinais , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Queratinócitos/metabolismo , Queratinócitos/efeitos dos fármacos , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Inibidores da Fosfodiesterase 4/farmacologia , Interleucina-33/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem CelularRESUMO
BACKGROUND: Itch is the most troublesome symptom of atopic dermatitis, and it is important to assess it appropriately for optimal treatment. We discussed issues regarding itch and the most appropriate methods of assessment at the Atopic Itch Consensus Meeting (AICOM), attended by physicians and researchers with expertise in itch treatment and research. METHODS: The AICOM participants prepared a draft consensus statement that addressed the most appropriate itch assessment methods for age groups <2 years, 2-6 years, 7-14 years, and ≥15 years. Consensus was defined as agreement by ≥80% of the participants. RESULTS: Votes were cast by 20 participants (8 dermatologists, 7 pediatricians, and 5 researchers), and a consensus on the best current methods of itch assessment was reached with 95% agreement. For infants and preschool children, because subjective evaluation is difficult, a checklist for itch assessment was developed for caregivers. CONCLUSION: For itch assessment, we recommend subjective evaluation by the patient using a rating scale. For infants and preschoolers, evaluation should be done by the caregiver using a checklist, combined with objective evaluation (of skin lesions, for example) by a physician. We anticipate that more objective itch assessment indices will be established in the future.
Assuntos
Dermatite Atópica , Prurido , Lactente , Pré-Escolar , Humanos , Índice de Gravidade de Doença , Prurido/diagnóstico , Prurido/etiologia , Dermatite Atópica/complicações , Dermatite Atópica/diagnóstico , Dermatite Atópica/terapiaRESUMO
Itching due to atopic dermatitis causes sleep disorders in children, but its pathology is unknown. The aim of this study is to investigate nocturnal scratching as an indirect index of itching during sleep and its relationship with depth of sleep in children with atopic dermatitis. Nocturnal scratching was measured in a total of 20 children with atopic dermatitis, using a smartwatch installed with the application Itch Tracker. Depth of sleep was analysed using polysomnography. The severity of atopic dermatitis was scored using Eczema Area and Severity Index (EASI) and Patient-Oriented Eczema Measure (POEM). The number and time of nocturnal scratching measured by Itch Tracker had a significantly positive correlation with EASI scores, whereas POEM scores were not correlated with EASI scores. Mean sleep efficiency was 90.0% and scratching episodes (n = 67) started mainly during the awake stage or light sleep stages. In the scratching episodes that started during sleep stages (n = 34), the sleep stage changed to a lighter one or to the awake stage in 35.5% of episodes. Itch Tracker is applicable to measure nocturnal scratching in children. Nocturnal scratching can deteriorate quality of sleep by changing the sleep stage to a lighter one or to the awake stage.
Assuntos
Dermatite Atópica , Eczema , Humanos , Criança , Dermatite Atópica/complicações , Dermatite Atópica/diagnóstico , Qualidade do Sono , Índice de Gravidade de Doença , Prurido/diagnóstico , Prurido/etiologia , SonoRESUMO
Interleukin (IL)-33 and IL-37 have been identified as novel cytokines involved in various inflammatory diseases. However, their specific roles remain largely unknown. Recent studies have shown that IL-33, which triggers inflammation, and IL-37, which suppresses it, cooperatively regulate the balance between inflammation and anti-inflammation. IL-33 and IL-37 are also deeply involved in the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. Furthermore, a signaling pathway by which aryl hydrocarbon receptor (AHR), a receptor for dioxins, regulates the expression of IL-33 and IL-37 has been revealed. Here, we outline recent findings on the mechanisms regulating IL-33 and IL-37 expression in AD and psoriasis. IL-33 expression is partially dependent on mitogen-activated protein kinase (MAPK) activation, and IL-37 has a role in suppressing MAPK in human keratinocytes. Furthermore, IL-33 downregulates skin barrier function proteins including filaggrin and loricrin, thereby downregulating the expression of IL-37, which colocalizes with these proteins. This leads to an imbalance of the IL-33-IL-37 axis, involving increased IL-33 and decreased IL-37, which may be associated with the pathogenesis of AD and psoriasis. Therefore, AHR-mediated regulation of the IL-33-IL-37 axis may lead to new therapeutic strategies for the treatment of AD and psoriasis.
Assuntos
Dermatite Atópica , Interleucina-1 , Interleucina-33 , Psoríase , Humanos , Dermatite Atópica/metabolismo , Inflamação/metabolismo , Interleucina-33/metabolismo , Queratinócitos/metabolismo , Psoríase/genética , Psoríase/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/metabolismo , Interleucina-1/metabolismoRESUMO
BACKGROUND: The Recap of atopic eczema (RECAP), a new core outcome of the atopic dermatitis trial, was translated into Japanese and linguistically validated. METHODS: Translation into Japanese was accomplished according to the ISPOR (International Society for Pharmacoeconomics and Outcome Research) guidelines and the basic guidelines for scale translation. The translation process included two forward translations, reconciliation with native English speakers, third-party back translation, cognitive debriefing, review and harmonization by the original authors. Twenty-seven atopic dermatitis and pediatric specialists from 21 centers in Japan participated in the translation process. Cognitive debriefing was conducted through face-to-face interviews using a think-aloud method with the interview guide including questions about comprehensibility, relevance, comprehensiveness, recall period and suggested improvements, based on the COSMIN methodology. RESULTS: No linguistic or cultural problems were encountered in the translation into Japanese. Cognitive debriefings were conducted with 10 adult patients and 10 parents of pediatric patients. Some minor modifications were made following discussion and approval by the research team and the original authors. The Japanese version of RECAP was considered to be understandable, comprehensive and relevant for adult patients and families of pediatric patients. CONCLUSION: The Japanese version of the RECAP, which has been validated as linguistically equivalent to the original version, is now available. Further evaluation of the measurement properties is needed in the future.
Assuntos
Dermatite Atópica , Adulto , Humanos , Criança , Japão , Dermatite Atópica/terapia , Inquéritos e Questionários , Linguística , TraduçõesRESUMO
BACKGROUND: IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibition of IL-31 production remain unexploited. IL-31 production by TH cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1. OBJECTIVE: We aimed at developing small-molecule inhibitors that selectively block IL-31 production by TH cells. METHODS: We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and we screened 9600 chemical compounds. The selected compounds were further examined by using TH cells from a spontaneous mouse model of AD and TH cells from patients with AD. RESULTS: We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL31 induction. Although IPHBA did not affect nonspecific T-cell proliferation, IPHBA inhibited antigen-induced IL-31 production by TH cells from both an AD mouse model and patients with AD without affecting other cytokine production and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31-producing TH cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited the association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of the IL31 promoter. We also determined the structure-activity relationship of IPHBA by synthesizing and analyzing 201 analogous compounds. CONCLUSION: IPHBA could be a potential drug leading to inhibition of EPAS1-driven IL-31 production.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Dermatite Atópica/imunologia , Doxiciclina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucinas/imunologia , Transdução de Sinais/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Dermatite Atópica/genética , Dermatite Atópica/patologia , Regulação da Expressão Gênica/imunologia , Interleucinas/genética , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-IndutoresRESUMO
Atopic dermatitis (AD) is an eczematous skin disorder characterized by type 2 inflammation, barrier disruption, and intense itch. In addition to type 2 cytokines, many other cytokines, such as interferon gamma (IFN-γ), interleukin 17 (IL-17), and interleukin 22 (IL-22), play roles in the pathogenesis of AD. It has been reported that the extracellular signal-regulated kinase (ERK) is downstream of such cytokines. However, the involvement of the ERK pathway in the pathogenesis of AD has not yet been investigated. We examined the expression of p-ERK in mouse and human AD skin. We also investigated the effects of the topical application of an ERK inhibitor on the dermatitis score, transepidermal water loss (TEWL), histological change, and expression of filaggrin, using an AD-like NC/Nga murine model. The effects of an ERK inhibitor on filaggrin expression in normal human epidermal keratinocytes (NHEKs) and on chemokine production from bone marrow-derived dendritic cells (BMDCs) were also evaluated. p-ERK was highly expressed in mouse and human AD skin. Topical application of an ERK inhibitor alleviated the clinical symptoms, histological changes, TEWL, and decrease in expression of filaggrin in the AD-like NC/Nga murine model. The ERK inhibitor also restored the IL-4 induced reduction in the expression of filaggrin in NHEK, and inhibited chemokine production from BMDC induced by IL-4. These results indicate that the ERK pathway is involved in the pathogenesis of AD, and suggest that the ERK pathway has potential as a therapeutic target for AD in the future.
Assuntos
Dermatite Atópica , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Interleucina-4/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Pele/metabolismoRESUMO
This is an abridged edition of English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. In Japan, from the perspective of evidence-based medicine, the current strategies for the treatment of AD consist of three primary measures: (i) use of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment as the main treatment of the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling, and advice about daily life. In the present revised guidelines, the description about three new drugs, namely, dupilumab, delgocitinib, and baricitinib, has been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.
Assuntos
Dermatite Atópica , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Emolientes/uso terapêutico , Glucocorticoides , Humanos , Japão , Pomadas/uso terapêutico , Tacrolimo/uso terapêuticoRESUMO
BACKGROUND: Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. METHODS: We analyzed the mite-induced AD-like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. RESULTS: Topical application of bosentan significantly attenuated the development of mite-induced AD-like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation-regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose- and time-dependent manner, bosentan treatment attenuated this. CONCLUSIONS: EDN1 plays a significant role in mite-induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.
Assuntos
Dermatite Atópica , Ácaros , Animais , Bosentana , Dermatite Atópica/tratamento farmacológico , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/farmacologia , Camundongos , Prurido/tratamento farmacológico , Prurido/etiologia , PeleRESUMO
BACKGROUND: Soy isoflavones and their metabolites such as equol have been associated with a reduced risk of hormone-sensitive tumors and metabolic syndromes. However, individual soy isoflavones and equol levels in atopic dermatitis remain uninvestigated. OBJECTIVE: The aim of this study is to compare the levels of urinary daidzein, genistein, and equol between atopic dermatitis patients and normal subjects and to examine the correlation between equol concentration and the severity of clinical symptoms. METHODS: A cross-sectional study was conducted at Akita University Hospital and Aso Iizuka Hospital in Japan. Fifty patients with confirmed atopic dermatitis diagnosis and 67 healthy controls were recruited. Daidzein, genistein, and equol in urine were measured by using a high-performance liquid chromatography-mass spectrometry system. RESULTS: Urinary equol levels were significantly lower in the atopic dermatitis patients than in the healthy controls (p = 0.002). The difference was particularly noticeable in young people (6-19 years, p < 0.001). No correlations were found between urinary equol levels and the severity of clinical symptoms and laboratory data in the atopic dermatitis patients. CONCLUSION: Equol levels in childhood might be involved in the development of atopic dermatitis.
Assuntos
Dermatite Atópica/epidemiologia , Dermatite Atópica/urina , Equol/urina , Fatores Etários , Biomarcadores , Estudos de Casos e Controles , Criança , Estudos Transversais , Dermatite Atópica/diagnóstico , Dermatite Atópica/etiologia , Suscetibilidade a Doenças , Feminino , Genisteína/urina , Humanos , Isoflavonas/urina , Masculino , Prevalência , Índice de Gravidade de Doença , Glycine max/efeitos adversosRESUMO
Psoriasis is a TNF-α/IL-23/IL-17A-mediated inflammatory skin disease that causes a significant socioeconomic burden in afflicted patients. IL-17A-producing immune cells, including Th17 cells, are crucial effector cells in the development of psoriasis. IL-17A stimulates epidermal keratinocytes to produce CCL20, which eventually recruits CCR6 + Th17 cells into the lesional skin. Thus, the CCL20/CCR6 axis works as a driving force that prepares an IL-17A-rich cutaneous milieu. In this review, we summarize the current research topics on the CCL20/CCR6 axis and the therapeutic intervention of this axis for psoriasis.
Assuntos
Quimiocina CCL20/metabolismo , Suscetibilidade a Doenças , Psoríase/etiologia , Psoríase/metabolismo , Receptores CCR6/metabolismo , Animais , Biomarcadores , Quimiocina CCL20/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Psoríase/diagnóstico , Psoríase/terapia , Receptores CCR6/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
The Patient-Oriented Eczema Measure (POEM, 0-28 points) is a self-assessed, repeatable measurement tool for measuring atopic dermatitis (AD) severity. How-ever, whether POEM score is influenced by allergic comorbidities and whether POEM's severity banding is applicable in web-based surveys for AD remain unclear. A web-based questionnaire survey was conducted in 329 patients with AD. POEM, self-reported severity of AD, and comorbidity of allergic diseases including asthma, pollen rhinitis, allergic conjunctivitis, and food allergy were assessed. POEM scores were not affected by a history of comorbid allergic diseases. The severity banding for POEM scores on the web-based survey was as follows: clear/almost clear = 0, mild = 1-8, moderate = 9-21, and severe/very severe = 22-28, which was comparable to previous banding. These results suggest that POEM is useful for determining AD severity, even in web-based surveys. Patients with POEM scores above 9 points may be grouped into moderate, severe, and very severe AD.
Assuntos
Dermatite Atópica/diagnóstico , Hipersensibilidade/diagnóstico , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Criança , Comorbidade , Conjuntivite Alérgica/diagnóstico , Feminino , Hipersensibilidade Alimentar/diagnóstico , Inquéritos Epidemiológicos , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Rinite Alérgica/diagnóstico , Autorrelato , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Members of the interleukin (IL)-36 family, IL-36α, IL-36ß and IL-36γ, are potent chemoattractive cytokines for neutrophils and eosinophils. IL-36 receptor antagonist (IL-36Ra) inhibits IL-36α, IL-36ß and IL-36γ activity. However, the immunohistological expression of IL-36α, IL-36ß, IL-36γ and IL-36Ra has never been addressed in normal follicles, folliculitis or eosinophilic pustular folliculitis (EPF). METHODS: We performed immunohistochemical staining for IL-36α, IL-36ß, IL-36γ and IL-36Ra using 10 cases of EPF, nine of non-specific folliculitis, 10 normal skin samples and 10 samples of normal follicles adjacent to a sebaceous naevus as a control. Two dermatologists, who were blind to the patient records, evaluated all of the slides. RESULTS: The immunoreactive IL-36α was hardly detected in the follicular epithelium and epidermis in the normal skin, folliculitis or EPF. The expression of IL-36ß, IL-36γ and IL-36Ra was augmented in both folliculitis and EPF compared with that in normal follicles. Negative correlations were detected between IL-36ß and IL-36Ra and between IL-36γ and IL-36Ra in normal follicles; however, these were absent in folliculitis. In contrast to normal follicles and folliculitis, a significant positive correlation between IL-36ß/γ and IL-36Ra was shown in EPF. CONCLUSIONS: The overexpression of IL-36ß, IL-36γ and IL-36Ra is an integral part of the inflammatory response of folliculitis and EPF. The coordinated expression of IL-36γ and IL-36Ra may be related to the pathomechanism of EPF.
Assuntos
Eosinofilia/metabolismo , Foliculite/metabolismo , Interleucina-1/metabolismo , Interleucinas/metabolismo , Dermatopatias Vesiculobolhosas/metabolismo , Estudos de Casos e Controles , Eosinofilia/etiologia , Eosinofilia/patologia , Foliculite/etiologia , Foliculite/patologia , Humanos , Dermatopatias Vesiculobolhosas/etiologia , Dermatopatias Vesiculobolhosas/patologia , Regulação para CimaRESUMO
The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6+ immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6+ cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.
Assuntos
Epiderme/metabolismo , Interleucina-17/genética , Queratinócitos/metabolismo , Psoríase/genética , Proliferação de Células/genética , Quimiocina CCL20/genética , Quimiocina CXCL1/genética , Quimiocina CXCL2/genética , Epiderme/patologia , Humanos , Interleucina-8/genética , Queratinócitos/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Psoríase/patologiaRESUMO
Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.
Assuntos
Diferenciação Celular , Dermatite Atópica/metabolismo , Interleucinas/metabolismo , Queratinócitos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Resorcinóis/farmacologia , Estilbenos/farmacologia , Células Cultivadas , Proteínas Filagrinas , Humanos , Interleucinas/genética , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Janus Quinases/metabolismo , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6+ interleukin (IL)-17A-producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)-independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.
Assuntos
Quimiocina CCL20/metabolismo , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Transdução de Sinais , Linhagem Celular , Receptores ErbB/antagonistas & inibidores , Humanos , Interleucina-17/metabolismo , Queratinócitos/patologia , Masculino , Fosforilação , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, barrier disruption, chronic pruritus and marked scratching. Th2 cytokines, especially IL-13, play a pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Rα and IL-13 Rα1. A second receptor, IL-13 Rα2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Rα2 is overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression. The scratch-induced IL-13 Rα2 upregulation may attenuate the IL-13-mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of another IL-13 Rα2 ligand, chitinase 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of increased IL-13 Rα2 levels remain elusive in AD. In this review, we summarize the recent topics on IL-13 Rα2 in atopic skin inflammation.
Assuntos
Dermatite Atópica/etiologia , Suscetibilidade a Doenças , Subunidade alfa1 de Receptor de Interleucina-13/genética , Animais , Biomarcadores , Citocinas/metabolismo , Dermatite Atópica/diagnóstico , Dermatite Atópica/metabolismo , Dermatite Atópica/terapia , Regulação da Expressão Gênica , Humanos , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
BACKGROUND: Pediatric atopic dermatitis (PAD) is a pluricausal disease and is frequently seen in dermatological and pediatric practice. Therefore, it is important to find common views in clinical practice and to promote consensus among practitioners. Aiming to obtain common views among dermatologists and pediatricians and to disseminate them widely in clinical practice, we held the PAD Consensus Forums described herein. METHODS: Questionnaire surveys of treatment goals and drug therapy were conducted to prepare topics for discussion at the PAD Consensus Forums. Reaching consensus was defined as agreement among at least 70% of the participants. RESULTS: As a result of discussion among 24 dermatologists and 25 pediatricians, consensus was obtained on 7 topics. These topics configure 3 consensus of treatment goals (Attainment targets were divided into the short/medium term and the long term. Attainment targets were associated with the primary evaluation domains of the Harmonising Outcome Measures for Eczema (HOME) roadmap, etc.) and 4 consensus of drug therapy (The number of applications of topical anti-inflammatory drugs in the acute phase and selection and ideal intervals between applications of topical anti-inflammatory drugs in proactive therapy, etc.). CONCLUSIONS: The consensus is expected to help practitioners set appropriate treatment goals in clinical practice and facilitate the choice of drugs for treatment.