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2.
Nat Immunol ; 21(11): 1359-1370, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32929274

RESUMO

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.


Assuntos
Asma/etiologia , Asma/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Receptor Notch4/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Alérgenos/imunologia , Análise de Variância , Asma/diagnóstico , Biomarcadores , Suscetibilidade a Doenças , Expressão Gênica , Via de Sinalização Hippo , Humanos , Tolerância Imunológica , Imunofenotipagem , Proteínas Serina-Treonina Quinases/metabolismo , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Via de Sinalização Wnt
4.
Allergy ; 77(11): 3377-3387, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35841382

RESUMO

BACKGROUND: The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (Treg ) cells in an IL-6-dependent manner. OBJECTIVE: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on Treg cells as a function of IL4RR576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on Treg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. RESULTS: Asthmatics carrying the IL4RR576 allele had increased Notch4 expression on their circulating Treg cells as a function of disease severity and serum IL-6. Mice harboring the Il4raR576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon Treg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung Treg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor. CONCLUSION: These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung Treg cell function.


Assuntos
Asma , Pneumonia , Animais , Camundongos , Asma/genética , Modelos Animais de Doenças , Inflamação , Interleucina-6/metabolismo , Leucócitos Mononucleares/metabolismo , Pulmão , Camundongos Endogâmicos BALB C , Pneumonia/metabolismo , Receptores de Interleucina-4/metabolismo , Linfócitos T Reguladores
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