RESUMO
BACKGROUND: The Duffy antigen receptor for chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown. OBJECTIVE: To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma. METHODS: Mice with targeted disruption of the Darc gene (Darc∆E2 ) or WT mice were challenged over 3 weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analysed in a cohort of poorly controlled asthmatics. RESULTS: Total airway inflammation following HDM did not differ between Darc∆E2 and WT mice. At 24 hours, Darc∆E2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in Darc∆E2 but persisted in WT mice. In poorly controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37-7.27), P=.0062). CONCLUSIONS AND CLINICAL RELEVANCE: Our animal model and human patient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.
Assuntos
Asma , Quimiocinas , Sistema do Grupo Sanguíneo Duffy , Receptores de Superfície Celular , Animais , Feminino , Humanos , Masculino , Camundongos , Antígenos de Dermatophagoides/imunologia , Asma/diagnóstico , Asma/etiologia , Asma/metabolismo , Quimiocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Sistema do Grupo Sanguíneo Duffy/genética , Sistema do Grupo Sanguíneo Duffy/metabolismo , Expressão Gênica , Loci Gênicos , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Aceitação pelo Paciente de Cuidados de Saúde , Avaliação de Resultados da Assistência ao Paciente , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Hipersensibilidade Respiratória/diagnóstico , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Índice de Gravidade de DoençaRESUMO
Myogenic differentiation involves myoblast fusion and induction of muscle-specific gene expression, which are both stimulated by pharmacological (LiCl), genetic, or IGF-I-mediated GSK-3ß inactivation. To assess whether stimulation of myogenic differentiation is common to ligand-mediated GSK-3ß inactivation, myoblast fusion and muscle-specific gene expression were investigated in response to Wnt-3a. Moreover, crosstalk between IGF-I/GSK-3ß/NFATc3 and Wnt/GSK-3ß/ß-catenin signaling was assessed. While both Wnt-3a and LiCl promoted myoblast fusion, muscle-specific gene expression was increased by LiCl, but not by Wnt-3a or ß-catenin over-expression. Furthermore, LiCl and IGF-I, but not Wnt-3a, increased NFATc3 transcriptional activity. In contrast, ß-catenin-dependent transcriptional activity was increased by Wnt-3a and LiCl, but not IGF-I. These results for the first time reveal a segregated regulation of myoblast fusion and muscle-specific gene expression following stimulation of myogenic differentiation in response to distinct ligand-specific signaling routes of GSK-3ß inactivation.
