内皮Sox17促进过敏性气道炎症
2019/04/19
摘要
背景：白细胞介素（IL）-33，已知在嗜酸性粒细胞性哮喘中增加并被认为作为其治疗靶点，激活内皮细胞中一种内皮特异性转录因子Sry相关的高迁移率族盒（Sox）17上调。我们使用小鼠气道炎症模型研究了Sox17和IL-33之间的关系，以及Sox17在哮喘发病机制中的可能作用。
方法：我们使用卵清蛋白（OVA）在内皮特异性Sox17无效突变小鼠中诱导气道炎症，并利用IL-33中和抗体来评估IL-33和Sox17之间的相互作用。我们评估了气道炎症，测量了各种细胞因子，趋化因子和粘附分子的水平。我们还在人内皮细胞中进行了Sox17的功能丧失或获得功能实验。
结果：在OVA激发小鼠的肺中IL-33和Sox17的表达水平显著增加。抗IL-33中和抗体治疗不仅减弱了OVA诱导的气道炎症，而且减弱了肺内皮细胞中Sox17的表达。重要的是，Sox17的内皮特异性缺失导致哮喘的各种临床特征的显著减轻，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缺失还导致肺中高Ly6c单核细胞和炎性DCs的密度降低。在IL-33刺激的人内皮细胞中，Sox17与CCL2和ICAM-1呈正相关。最后，Sox17促进单核细胞与内皮细胞的粘附，并上调ERK-STAT3通路。
结论：Sox17受IL-33调节，其在内皮细胞中的基因消除导致哮喘相关病理生理特征的减轻。Sox17可能是哮喘管理的潜在目标。
Endothelial Sox17 promotes allergic airway inflammation.
Ha EH, Choi JP, Kwon HS, Park HJ, Lah SJ, Moon KA, Lee SH, Kim I, Cho YS.
Abstract
BACKGROUND:Interleukin (IL)-33, known to be increased in eosinophilic asthma and suggested as a therapeutic target for it, activates endothelial cells in which Sry-related high-mobility-group box (Sox) 17, an endothelial-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.
METHODS:We used ovalbumin (OVA) to induce airway inflammation in endothelium-specific Sox17 null mutant mice, and utilized IL-33 neutralizing antibody to evaluate the interplay between IL-33 and Sox17. We evaluated the airway inflammation, measured the 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:The levels of IL-33 and Sox17 expression 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 DCs in the lungs. In IL-33-stimulated human endothelial cells, Sox17 showed positive correlation with CCL2 and ICAM-1. Lastly, Sox17 promoted monocytes adhesion to endothelial cells, and upregulated the ERK-STAT3 pathway.
CONCLUSIONS:Sox17 was regulated by IL-33, and its genetic ablation in endothelial cells resulted in alleviation of asthma-related pathophysiologic features. Sox17 may be a potential target for asthma management.
背景：白细胞介素（IL）-33，已知在嗜酸性粒细胞性哮喘中增加并被认为作为其治疗靶点，激活内皮细胞中一种内皮特异性转录因子Sry相关的高迁移率族盒（Sox）17上调。我们使用小鼠气道炎症模型研究了Sox17和IL-33之间的关系，以及Sox17在哮喘发病机制中的可能作用。
方法：我们使用卵清蛋白（OVA）在内皮特异性Sox17无效突变小鼠中诱导气道炎症，并利用IL-33中和抗体来评估IL-33和Sox17之间的相互作用。我们评估了气道炎症，测量了各种细胞因子，趋化因子和粘附分子的水平。我们还在人内皮细胞中进行了Sox17的功能丧失或获得功能实验。
结果：在OVA激发小鼠的肺中IL-33和Sox17的表达水平显著增加。抗IL-33中和抗体治疗不仅减弱了OVA诱导的气道炎症，而且减弱了肺内皮细胞中Sox17的表达。重要的是，Sox17的内皮特异性缺失导致哮喘的各种临床特征的显著减轻，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缺失还导致肺中高Ly6c单核细胞和炎性DCs的密度降低。在IL-33刺激的人内皮细胞中，Sox17与CCL2和ICAM-1呈正相关。最后，Sox17促进单核细胞与内皮细胞的粘附，并上调ERK-STAT3通路。
结论：Sox17受IL-33调节，其在内皮细胞中的基因消除导致哮喘相关病理生理特征的减轻。Sox17可能是哮喘管理的潜在目标。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2019 Mar 27. pii: S0091-6749(19)30414-2. doi: 10.1016/j.jaci.2019.02.034. [Epub ahead of print])
(J Allergy Clin Immunol. 2019 Mar 27. pii: S0091-6749(19)30414-2. doi: 10.1016/j.jaci.2019.02.034. [Epub ahead of print])
Endothelial Sox17 promotes allergic airway inflammation.
Ha EH, Choi JP, Kwon HS, Park HJ, Lah SJ, Moon KA, Lee SH, Kim I, Cho YS.
Abstract
BACKGROUND:Interleukin (IL)-33, known to be increased in eosinophilic asthma and suggested as a therapeutic target for it, activates endothelial cells in which Sry-related high-mobility-group box (Sox) 17, an endothelial-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.
METHODS:We used ovalbumin (OVA) to induce airway inflammation in endothelium-specific Sox17 null mutant mice, and utilized IL-33 neutralizing antibody to evaluate the interplay between IL-33 and Sox17. We evaluated the airway inflammation, measured the 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:The levels of IL-33 and Sox17 expression 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 DCs in the lungs. In IL-33-stimulated human endothelial cells, Sox17 showed positive correlation with CCL2 and ICAM-1. Lastly, Sox17 promoted monocytes adhesion to endothelial cells, and upregulated the ERK-STAT3 pathway.
CONCLUSIONS:Sox17 was regulated by IL-33, and its genetic ablation in endothelial cells resulted in alleviation of asthma-related pathophysiologic features. Sox17 may be a potential target for asthma management.
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通过气道蛋白质组学特征对哮喘表型进行分层
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性激素影响哮喘发展的遗传和观察证据
