Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Asan Institute for Life Science, Seoul, Korea.
J Allergy Clin Immunol. 2019 Aug;144(2):561-573.e6. doi: 10.1016/j.jaci.2019.02.034. Epub 2019 Mar 28.
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.
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.
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.
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 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.
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.
白细胞介素 33（IL-33）在嗜酸性粒细胞性哮喘患者中的水平升高，被认为是其治疗靶点。它可激活内皮细胞，使其中的性别决定区 Y 框蛋白 17（Sox17）这种内皮细胞特异性转录因子表达上调。
我们通过气道炎症的小鼠模型，研究 Sox17 与 IL-33 之间的关系，以及 Sox17 在哮喘发病机制中的可能作用。
我们使用卵清蛋白（OVA）诱导内皮细胞特异性 Sox17 缺失突变小鼠的气道炎症，并使用 IL-33 中和抗体评估 IL-33 和 Sox17 之间的相互作用。我们评估气道炎症并测量各种细胞因子、趋化因子和黏附分子的水平。我们还在人内皮细胞中进行 Sox17 的功能获得或缺失实验。
OVA 激发的小鼠肺部的 IL-33 和 Sox17 水平显著升高。抗 IL-33 中和抗体治疗不仅减轻了 OVA 诱导的气道炎症，还减轻了肺内皮细胞中 Sox17 的表达。重要的是，内皮细胞特异性 Sox17 缺失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。Sox17 缺失还导致肺中 Ly6c 单核细胞和炎症性树突状细胞的密度降低。在 IL-33 刺激的人内皮细胞中，Sox17 与 CCL2 和细胞间黏附分子 1 水平呈正相关。最后，Sox17 促进单核细胞与内皮细胞的黏附，并上调细胞外信号调节激酶-信号转导和转录激活因子 3 通路。
Sox17 受 IL-33 调控，内皮细胞中 Sox17 的遗传缺失可减轻与哮喘相关的病理生理特征。Sox17 可能是哮喘管理的潜在靶点。
