Combined blockade of IL-25, IL-33 and TSLP mediates amplified inhibition of airway inflammation and remodelling in a murine model of asthma
Combined blockade of IL-25, IL-33 and TSLP mediates amplified inhibition of airway inflammation and remodelling in a murine model of asthma
复制标题
联合阻断 IL-25、IL-33 和 TSLP 可增强小鼠哮喘模型中气道炎症和重塑的抑制作用
DOI：
10.1111/resp.13711
复制
发表时间：
2020-06-01
期刊：
影响因子：
6.9
通讯作者：
Ying, Sun
中科院分区：
文献类型：
--
作者：
An, Gao;Wang, Wenjun;Ying, Sun
背景与目的孤立阻断IL-25、IL-33和胸腺基质淋巴生成素（TSLP）可减轻小鼠哮喘模型气道炎症和高反应性。联合阻断所有三种细胞因子可以更有效地完成这一假设从未得到解决。方法采用卵清蛋白（OVA）致敏和生理盐水刺激小鼠哮喘模型。为了辨别IL-33阻断的影响，我们比较了同种、野生型和IL-33受体（St2(-/-)）基因缺失小鼠的结果。然后，我们在St2（-/-）动物中检测了用阻断抗体单独或联合阻断IL-25和TSLP的效果。结果包括气道反应性、炎症细胞浸润、上皮细胞化生、纤维化相关蛋白沉积、局部th2型细胞因子表达以及ELISA和定量免疫组织化学测定的血清总IgE和特异性IgE浓度。结果St2（-/-）基因缺失显著降低气道反应性、炎症细胞浸润、肺组织中Th2细胞因子、纤维化相关蛋白和血清总IgE的表达。对St2（-/-）小鼠额外给予抗il -25和抗tslp阻断抗体进一步显著降低炎症、Th2细胞因子表达、气道纤维化和IgE产生，而抗tslp单独降低嗜酸性粒细胞浸润和局部IL-4表达。在同型相同的对照抗体存在下，气道炎性细胞浸润和肺组织中Th2细胞因子而非纤维化相关蛋白的表达也降低。结论联合阻断这三种细胞因子可更好地改善小鼠哮喘模型气道的病理改变，对人类哮喘也有一定的指导意义。
Background and objective Isolated blockade of IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) has been shown to reduce airways inflammation and hyperresponsiveness in murine asthma model. The hypothesis that combined blockade of all three cytokines can accomplish this more effectively has never been addressed.Methods We studied a murine asthma model employing sensitization and challenge with ovalbumin (OVA) or saline control. To discern the effects of IL-33 blockade, we compared outcomes in strain identical, wild-type and IL-33 receptor (St2( -/-)) gene-deleted mice. We then examined, in the St2( -/-) animals, the effects of additional, single or combined blockade of IL-25 and TSLP with blocking antibodies. Outcomes included airways reactivity, inflammatory cellular infiltration, epithelial cell metaplasia, deposition of fibrosis-related proteins, local Th2-type cytokine expression and total and specific serum IgE concentrations measured by ELISA and quantitative immunohistochemistry.Results St2( -/-) gene deletion significantly reduced airways reactivity, inflammatory cellular infiltration, lung tissue expression of Th2 cytokines and fibrosis related proteins and serum total IgE in response to OVA sensitization and challenge. Additional administration of anti-IL-25 and anti-TSLP blocking antibodies to the St2( -/-) mice further significantly reduced inflammation, Th2 cytokine expression, airways fibrosis and IgE production, while anti-TSLP alone reduced eosinophil infiltration and local IL-4 expression. The airways inflammatory cellular infiltrate and lung tissue expression of Th2 cytokine, but not fibrosis-related proteins were also reduced in the presence of isotype identical, control antibodies.Conclusion Combined blockade of these three cytokines may better ameliorate airways pathological changes in this murine asthma model, with implications for human asthma.