RESUMO
ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12-hydroxyeicosapentaenoic acid (12-HEPE), which is a 12-lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid-rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12-HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12-HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12-HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12-HEPE as the dominant ω3 fatty acid metabolite in the skin.
Assuntos
Quimiocina CXCL1/metabolismo , Dermatite de Contato/prevenção & controle , Ácido Eicosapentaenoico/análogos & derivados , Queratinócitos/efeitos dos fármacos , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/metabolismo , Células da Medula Óssea , Quimiocina CXCL1/genética , Dieta , Dinitrofluorbenzeno , Regulação para Baixo , Ácido Eicosapentaenoico/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células HaCaT , Humanos , Óleo de Semente do Linho/administração & dosagem , Óleo de Semente do Linho/metabolismo , CamundongosRESUMO
Dietary lipids are fundamental nutrients for human health. They are typically composed of various long-chain fatty acids which include saturated fatty acids (SFAs) and unsaturated fatty acids (UFAs). UFAs are further classified into several groups, such as omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs, depending on their chemical structure. Epidemiological studies have suggested the involvement of dietary lipids in the progression or regulation of psoriasis, a common chronic inflammatory skin disease induced via the IL-23/IL-17 axis. Although the underlying mechanisms by which dietary lipids regulate psoriasis have remained unclear, with the advancement of experimental techniques and the development of psoriasis mouse models, various possible mechanisms have been proposed. For example, SFAs may facilitate psoriatic dermatitis by causing activation of the inflammasome in keratinocytes and macrophages or by inducing IL-17-producing cells, such as Th17 and IL-17-producing γδ T cells in the skin, while omega-3 PUFAs may play inhibitory roles by suppressing Th17 differentiation. In this review, we summarize current data on the roles of dietary lipids in the development of psoriasis as revealed by mouse studies, and we discuss potential therapeutic strategies for psoriasis from the perspective of dietary lipids.
Assuntos
Gorduras na Dieta/imunologia , Psoríase/imunologia , Transdução de Sinais/imunologia , Animais , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Inflamassomos/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Psoríase/patologia , Pele/citologia , Pele/imunologia , Pele/patologia , Células Th17/imunologiaRESUMO
The potential of omega-3 poly-unsaturated fatty acids (PUFAs) as a therapeutic target for psoriasis, a chronic inflammatory skin disease of IL-23/IL-17 axis, is a long-disputed question, since various epidemiological studies have suggested the association between high-intake of omega-3 PUFAs and the reduced frequency and severity of psoriasis. However, their actual significance and the molecular mechanisms remain largely unknown. To address these issues, we focused on resolvin E1 (RvE1), an omega-3 PUFAs-derived metabolite, and examined its effects on psoriatic dermatitis, using an imiquimod-induced mouse psoriasis model. RvE1 potently suppressed the inflammatory cell infiltration and epidermal hyperplasia in the psoriatic skin. RvE1 decreased the mRNA expression of IL-23 in the skin. Consistently, RvE1 inhibited IL-23 production by dendritic cells (DCs) in vitro. Furthermore, RvE1 exerted inhibitory effects on migration of cutaneous DCs and γδ T cells, a major IL-17-producing cell population in mouse, both in vivo and in vitro. These suppressive effects of RvE1 were mediated by its antagonistic function on BLT1, a receptor of leukotriene B4, and were also observed in human DCs, Th17 and Tc17 cells. Our results indicate a novel mechanism of omega-3 PUFA-mediated amelioration of psoriasis, and suggest a potential of RvE1 as a therapeutic target for psoriasis.
Assuntos
Dermatite/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Psoríase/tratamento farmacológico , Animais , Movimento Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Dermatite/metabolismo , Modelos Animais de Doenças , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-17/metabolismo , Leucotrieno B4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismoRESUMO
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.
Assuntos
Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/fisiopatologia , Administração Tópica , Corticosteroides/uso terapêutico , Azatioprina/uso terapêutico , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Doença Crônica/epidemiologia , Doença Crônica/terapia , Dermatite Atópica/epidemiologia , Proteínas Filagrinas , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Imunossupressores/uso terapêutico , Proteínas de Filamentos Intermediários/análise , Proteínas de Filamentos Intermediários/genética , Metotrexato/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Qualidade de Vida/psicologia , Índice de Gravidade de Doença , Urticária/etiologia , Urticária/genéticaRESUMO
Alopecia areata (AA) is a common and stressful disorder that results in hair loss, and resistant to treatment in some cases. Experimental and clinical evidence suggests that AA is caused by autoimmune attack against the hair follicles. The precise pathomechanism, however, remains unknown. Here, we focus on the recent progress in multidisciplinary approaches to the epidemiology, pathogenesis, and new treatments of AA in 996 publications from January 2010 to July 2016, and provide an overview of the current understanding in clinical management and research directions.
Assuntos
Alopecia em Áreas/epidemiologia , Alopecia em Áreas/etiologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Folículo Piloso/imunologia , Administração Tópica , Alopecia em Áreas/diagnóstico , Alopecia em Áreas/terapia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Biomarcadores/sangue , Quimiocinas/imunologia , Crioterapia , Dermoscopia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Imunoterapia/métodos , Incidência , Fototerapia , Guias de Prática Clínica como Assunto , Pulsoterapia , Qualidade de Vida , Linfócitos T Reguladores/imunologiaRESUMO
Particulate pollution is thought to function as an adjuvant that can induce allergic responses. However, the exact cell types and immunological factors that initiate the lung-specific immune responses are unclear. We found that upon intratracheal instillation, particulates such as aluminum salts and silica killed alveolar macrophages (AMs), which then released interleukin-1α (IL-1α) and caused inducible bronchus-associated lymphoid tissue (iBALT) formation in the lung. IL-1α release continued for up to 2 weeks after particulate exposure, and type-2 allergic immune responses were induced by the inhalation of antigen during IL-1α release and iBALT formation, even long after particulate instillation. Recombinant IL-1α was sufficient to induce iBALTs, which coincided with subsequent immunoglobulin E responses, and IL-1-receptor-deficient mice failed to induce iBALT formation. Therefore, the AM-IL-1α-iBALT axis might be a therapeutic target for particulate-induced allergic inflammation.
Assuntos
Brônquios/imunologia , Interleucina-1alfa/imunologia , Tecido Linfoide/imunologia , Macrófagos Alveolares/patologia , Material Particulado/toxicidade , Compostos de Alumínio/toxicidade , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Dióxido de Silício/toxicidadeRESUMO
BACKGROUND: Using JAK inhibitors to inhibit cytokine signaling is presumed to be a possible means of treating skin inflammatory disorders such as contact dermatitis. OBJECTIVE: To clarify the action site of JAK inhibitors in skin inflammatory disorders. METHODS: We analyzed the mechanism of action of the JAK inhibitor JTE-052 using murine skin inflammation models, including contact hypersensitivity (CHS) and irritant contact dermatitis. Cells isolated from ear tissue or lymph node (LN) were analyzed by flow cytometry. The amounts of cytokines in the culture medium were measured by ELISA or bead array system. Proliferation of LN cells was evaluated by measurement of tritiated thymidine incorporation. RESULTS: Oral administration of JTE-052 during both sensitization and elicitation phase attenuated CHS, but did not affect croton oil-induced irritant contact dermatitis. JTE-052 potently inhibited T cell proliferation and activation by antigen presentation in vitro, and attenuated skin inflammation in a sensitized-lymphocyte transfer model without suppressing T cell migration. JTE-052 did not affect hapten-induced cutaneous dendritic cell migration into draining lymph nodes or their costimulatory molecule expressions. CONCLUSION: The JAK inhibitor JTE-052 exerts an inhibitory effect on antigen-specific T cell activation and subsequent inflammation in acquired skin immunity, such as CHS.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Dermatite Alérgica de Contato/tratamento farmacológico , Ativação Linfocitária , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Linfócitos T/citologia , Administração Oral , Animais , Apresentação de Antígeno , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Óleo de Cróton , Células Dendríticas/citologia , Dermatite Alérgica de Contato/imunologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Haptenos/imunologia , Inflamação , Interferon gama/metabolismo , Interleucina-13/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pele/imunologia , Pele/patologiaRESUMO
Eosinophilic pustular folliculitis (EPF) is a non-infectious inflammatory dermatosis of unknown etiology that principally affects the hair follicles. There are three variants of EPF: (i) classic EPF; (ii) immunosuppression-associated EPF, which is subdivided into HIV-associated (IS/HIV) and non-HIV-associated (IS/non-HIV); and (iii) infancy-associated EPF. Oral indomethacin is efficacious, especially for classic EPF. No comprehensive information on the efficacies of other medical management regimens is currently available. In this study, we surveyed regimens for EPF that were described in articles published between 1965 and 2013. In total, there were 1171 regimens; 874, 137, 45 and 115 of which were applied to classic, IS/HIV, IS/non-HIV and infancy-associated EPF, respectively. Classic EPF was preferentially treated with oral indomethacin with efficacy of 84% whereas topical steroids were preferred for IS/HIV, IS/non-HIV and infancy-associated EPF with efficacy of 47%, 73% and 82%, respectively. Other regimens such as oral Sairei-to (a Chinese-Japanese herbal medicine), diaminodiphenyl sulfone, cyclosporin and topical tacrolimus were effective for indomethacin-resistant cases. Although the preclusion of direct comparison among cases was one limitation, this study provides a dataset that is applicable to the construction of therapeutic algorithms for EPF.
Assuntos
Eosinofilia/tratamento farmacológico , Foliculite/tratamento farmacológico , Dermatopatias Vesiculobolhosas/tratamento farmacológico , Adulto , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Eosinofilia/classificação , Eosinofilia/etiologia , Foliculite/classificação , Foliculite/etiologia , Infecções por HIV/complicações , Humanos , Terapia de Imunossupressão/efeitos adversos , Indometacina/uso terapêutico , Lactente , Fitoterapia , Remissão Espontânea , Dermatopatias Vesiculobolhosas/classificação , Dermatopatias Vesiculobolhosas/etiologia , Esteroides/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Although eosinophils have been detected in several human skin diseases in the vicinity of basophils, how eosinophils infiltrate the skin and the role of eosinophils in the development of skin inflammation have yet to be examined. OBJECTIVE: Using murine irritant contact dermatitis (ICD) as a model, we sought to clarify the roles of eosinophils in ICD and the underlying mechanism of eosinophil infiltration of the skin. METHODS: We induced croton oil-induced ICD in eosinophil-deficient ΔdblGATA mice with or without a reactive oxygen species (ROS) inhibitor. We performed cocultivation with fibroblasts and bone marrow-derived basophils and evaluated eosinophil migration using a chemotaxis assay. RESULTS: ICD responses were significantly attenuated in the absence of eosinophils or by treatment with the ROS inhibitor. ROS was produced abundantly by eosinophils, and both basophils and eosinophils were detected in human and murine ICD skin lesions. In coculture experiments, basophils attracted eosinophils, especially in the presence of fibroblasts. Moreover, basophils produced IL-4 and TNF-α in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts in vitro. CONCLUSION: Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novel concept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the development of skin inflammation.
Assuntos
Basófilos/imunologia , Dermatite Atópica/imunologia , Eosinófilos/imunologia , Pele/imunologia , Animais , Basófilos/patologia , Comunicação Celular , Quimiocina CCL11/genética , Quimiocina CCL11/imunologia , Quimiotaxia , Técnicas de Cocultura , Óleo de Cróton , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/genética , Dermatite Atópica/patologia , Modelos Animais de Doenças , Eosinófilos/patologia , Fibroblastos/imunologia , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Irritantes , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/imunologia , Transdução de Sinais , Pele/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Zinc deficiency can be an inherited disorder, in which case it is known as acrodermatitis enteropathica (AE), or an acquired disorder caused by low dietary intake of zinc. Even though zinc deficiency diminishes cellular and humoral immunity, patients develop immunostimulating skin inflammation. Here, we have demonstrated that despite diminished allergic contact dermatitis in mice fed a zinc-deficient (ZD) diet, irritant contact dermatitis (ICD) in these mice was more severe and prolonged than that in controls. Further, histological examination of ICD lesions in ZD mice revealed subcorneal vacuolization and epidermal pallor, histological features of AE. Consistent with the fact that ATP release from chemically injured keratinocytes serves as a causative mediator of ICD, we found that the severe ICD response in ZD mice was attenuated by local injection of soluble nucleoside triphosphate diphosphohydrolase. In addition, skin tissue from ZD mice with ICD showed increased levels of ATP, as did cultured wild-type keratinocytes treated with chemical irritants and the zinc-chelating reagent TPEN. Interestingly, numbers of epidermal Langerhans cells (LCs), which play a protective role against ATP-mediated inflammatory signals, were decreased in ZD mice as well as samples from ZD patients. These findings suggest that upon exposure to irritants, aberrant ATP release from keratinocytes and impaired LC-dependent hydrolysis of nucleotides may be important in the pathogenesis of AE.
Assuntos
Acrodermatite/patologia , Acrodermatite/fisiopatologia , Dermatite Alérgica de Contato/patologia , Dermatite Alérgica de Contato/fisiopatologia , Células de Langerhans/imunologia , Pele/citologia , Zinco/deficiência , Acrodermatite/dietoterapia , Trifosfato de Adenosina/metabolismo , Animais , Células Cultivadas , Quimiocinas/genética , Quimiocinas/metabolismo , Dermatite Alérgica de Contato/dietoterapia , Suplementos Nutricionais , Feminino , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Células de Langerhans/citologia , Camundongos , Camundongos Endogâmicos BALB C , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Mycosis fungoides (MF) is a T cell neoplasm with elevation of serum Th2 chemokines. Although interferon-gamma (IFN-gamma) administration and narrowband-UVB (NB-UVB) phototherapy are used for the treatment of MF, a combination therapy of these two modalities is not fully established. OBJECTIVES: To define whether the combination of IFN-gamma and NB-UVB affects the balance of serum levels of Th1 and Th2 chemokines in patients with MF. METHODS: Twelve patients with MF received intravenous or intramuscular injections of recombinant IFN-gamma (rIFN-gamma) or natural IFN-gamma (nIFN-gamma) in combination with NB-UVB phototherapy. As control, three MF patients were treated with NB-UVB monotherapy. At the beginning and cessation of therapy, the concentrations of serum Th2 chemokines, TARC/CCL17 and MDC/CCL22, and Th1 chemokines, IP-10/CXCL10 and MIG/CXCL9 were measured by ELISA. RESULTS: Before treatment, not only Th2 chemokines but also Th1 chemokines were elevated in the patients. Whereas no significant changes were observed in the levels of TARC and MDC, IP-10 and MIG were further elevated by the combination of IFN-gamma and NB-UVB. On the other hand, NB-UVB monotherapy did not change the level of either Th1 or Th2 chemokine. CONCLUSIONS: The combination of IFN-gamma and NB-UVB elevated serum Th1 chemokines but unaffected Th2 chemokines. Since NB-UVB monotherapy could not affect the chemokine levels, the effect of the combination therapy is attributable to IFN-gamma. Given the role of Th1 chemokines for tumor-attacking T cell recruitment at the early stage of MF, the therapy may exert a beneficial effect for early MF.