Endothelial Sox17 promotes allergic airway inflammation
Endothelial Sox17 promotes allergic airway inflammation
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内皮Sox17促进过敏性气道炎症
DOI：
10.1016/j.jaci.2019.02.034
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发表时间：
2019-08-01
影响因子：
14.2
通讯作者：
Cho, You Sook
中科院分区：
文献类型：
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作者：
Ha, Eun Hee;Choi, Jun-Pyo;Cho, You Sook
背景资料：已知IL-33的水平在嗜酸性粒细胞性哮喘患者中升高并且被建议作为其治疗靶点，IL-33激活内皮细胞，其中Sry相关高迁移率族盒（Sox）17（内皮特异性转录因子）被上调。我们使用小鼠气道炎症模型研究了Sox 17和IL-33之间的关系以及Sox 17在哮喘发病机制中的可能作用。我们使用卵清蛋白（OVA）诱导内皮特异性Sox 17无效突变小鼠的气道炎症，并使用IL-33中和抗体来评估IL-33和Sox 17之间的相互作用。我们评估了气道炎症并测量了各种细胞因子、趋化因子和粘附分子的水平。结果：OVA攻击小鼠肺组织中IL-33和Sox 17的表达水平显著升高。抗IL-33中和抗体治疗不仅减弱了OVA诱导的气道炎症，还减弱了肺内皮细胞中Sox 17的表达。重要的是，内皮特异性缺失Sox 17导致哮喘的各种临床特征显著缓解，包括气道炎症、免疫细胞浸润、细胞因子/趋化因子产生和气道高反应性。Sox 17缺失还导致肺中Ly 6c（高）单核细胞和炎性树突状细胞密度降低。在IL-33刺激的人内皮细胞中，Sox 17与CCL 2和细胞间粘附分子1水平呈正相关。结论：IL-33对Sox 17的表达具有调节作用，其基因表达的缺失可减轻哮喘的病理生理学改变。Sox 17可能是哮喘管理的潜在靶点。
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 Ly6c(high) 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.