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1.
J Allergy Clin Immunol ; 144(2): 561-573.e6, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30928652

RESUMO

BACKGROUND: IL-33, levels of which are known to be increased in patients with eosinophilic asthma and which is suggested as a therapeutic target for it, activates endothelial cells in which Sry-related high-mobility-group box (Sox) 17, an endothelium-specific transcription factor, was upregulated. OBJECTIVE: We investigated the relationship between Sox17 and IL-33 and the possible role of Sox17 in the pathogenesis of asthma using a mouse model of airway inflammation. METHODS: We used ovalbumin (OVA) to induce airway inflammation in endothelium-specific Sox17 null mutant mice and used IL-33 neutralizing antibody to evaluate the interplay between IL-33 and Sox17. We evaluated airway inflammation and measured levels of various cytokines, chemokines, and adhesion molecules. We also carried out loss- or gain-of-function experiments for Sox17 in human endothelial cells. RESULTS: Levels of IL-33 and Sox17 were significantly increased in the lungs of OVA-challenged mice. Anti-IL-33 neutralizing antibody treatment attenuated not only OVA-induced airway inflammation but also Sox17 expression in pulmonary endothelial cells. Importantly, endothelium-specific deletion of Sox17 resulted in significant alleviation of various clinical features of asthma, including airway inflammation, immune cell infiltration, cytokine/chemokine production, and airway hyperresponsiveness. Sox17 deletion also resulted in decreased densities of Ly6chigh monocytes and inflammatory dendritic cells in the lungs. In IL-33-stimulated human endothelial cells, Sox17 showed positive correlation with CCL2 and intercellular adhesion molecule 1 levels. Lastly, Sox17 promoted monocyte adhesion to endothelial cells and upregulated the extracellular signal-regulated kinase-signal transducer and activator of transcription 3 pathway. CONCLUSION: Sox17 was regulated by IL-33, and its genetic ablation in endothelial cells resulted in alleviation of asthma-related pathophysiologic features. Sox17 might be a potential target for asthma management.


Assuntos
Asma/imunologia , Endotélio Vascular/imunologia , Proteínas HMGB/imunologia , Pulmão/imunologia , Fatores de Transcrição SOXF/imunologia , Animais , Asma/genética , Asma/patologia , Quimiocinas/genética , Quimiocinas/imunologia , Endotélio Vascular/patologia , Proteínas HMGB/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-33/genética , Interleucina-33/imunologia , Pulmão/patologia , Camundongos , Camundongos Mutantes , Fatores de Transcrição SOXF/genética
2.
Sci Rep ; 7: 41744, 2017 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-28134325

RESUMO

Basophils are rare, circulating granulocytes proposed to be involved in T helper (TH) type 2 immunity, mainly through secretion of interleukin (IL)-4. In addition to IL-4, basophils produce IL-6 and tumor necrosis factor (TNF)-α in response to immunoglobulin E (IgE) crosslinking. Differentiation of TH17 cells requires IL-6 and transforming growth factor (TGF)-ß, but whether basophils play a significant role in TH17 induction is unknown. Here we show a role for basophils in TH17 cell development by using in vitro T cell differentiation and in vivo TH17-mediated inflammation models. Bone marrow derived-basophils (BMBs) and splenic basophils produce significant amounts of IL-6 as well as IL-4 following stimulation with IgE crosslink or cholera toxin (CT). In addition, through IL-6 secretion, BMBs cooperate with dendritic cells to promote TH17 cell differentiation. In the TH17 lung inflammation model, basophils are recruited to the inflamed lungs following CT challenge, and TH17 responses are significantly reduced in the absence of basophils or IL-6. Furthermore, reconstitution with wild-type, but not IL-6-deficient, basophils restored CT-mediated lung inflammation. Lastly, basophil-deficient mice showed reduced phenotypes of TH17-dependent experimental autoimmune encephalomyelitis. Therefore, our results indicate that basophils are an important inducer of TH17 cell differentiation, which is dependent on IL-6 secretion.


Assuntos
Basófilos/imunologia , Basófilos/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/imunologia , Interleucina-6/metabolismo , Células Th17/citologia , Células Th17/fisiologia , Animais , Biomarcadores , Toxina da Cólera/efeitos adversos , Citocinas/biossíntese , Modelos Animais de Doenças , Imunidade , Imunofenotipagem , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/deficiência , Camundongos , Camundongos Knockout
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