气道上皮—嗜碱性粒细胞轴调控气道炎症的区域免疫特性研究

结题报告

项目介绍

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基本信息

批准号：
91542202
项目类别：
重大研究计划
资助金额：
252.0万
负责人：
夏振炜
依托单位：
上海交通大学
学科分类：
H0104.支气管哮喘
结题年份：
2019
批准年份：
2015
项目状态：
已结题
起止时间：
2016-01-01 至2019-12-31

项目参与者：
吕婕；邸彩霞；张彦洁；林晓亮；闾佳佳；袁煜凡；周光炎；
关键词：
TSLP 气道上皮细胞 OX40L/CD40 支气管哮喘嗜碱性粒细胞

项目摘要

Asthma is a disease involving dysregulated immune system. The lung, which is composed of airway epithelial cells and others, is a unique immune organ that is constantly exposed to airborne antigens. The airway epithelia in lung directly interact with airborne antigens and induce immune responses through the secretion of thymic stromal lymphopoietin (TSLP). Basophils, which function as immune cells in asthma, can be directly activated by TSLP. In our previous studies, we have demonstrated that depletion of basophils using specified antibodies could significantly attenuate the airway inflammation accompanying with decreased levels of Th2 cytokines in an OVA-induced allergic asthma model. Recently, we further found that OX40L and CD40 on basophils were highly expressed in an asthmatic model. Taken together, we suppose that the airway epithelium-basophil axis may be critical in the initiation of allergic airway inflammation. In this study, we plan to elucidate that airway epithelium can express TLR2 after OVA stimulation and secrete TSLP, which interacts with basophils to induce Th2 immune response through OX40/OX40L and CD40/CD40L pathways. We aim to investigate the pathogenesis mechanism of asthma, thus to provide for a potential immune therapy targets for this disease.

免疫调节异常是哮喘发病的重要机制。肺脏系非传统免疫器官，具有并形成独特免疫细胞及区域免疫特性。气道黏膜上皮为执行区域免疫主要场所，通过分泌胸腺基质淋巴生成素（TSLP）参与启动气道炎症。近年关注的嗜碱性粒细胞（Basophils，Ba）具有专职免疫细胞作用，在过敏原激发后Ba明显上调TSLP受体表达并受之调节。我们发现剔除Ba后OVA诱导的Th2免疫反应及气道炎症显著减轻，肺脏Th2型细胞因子水平降低；近期我们又发现哮喘期Ba能高表达OX40L和CD40。由此假设气道上皮细胞和Ba交互作用并通过OX40L和CD40始动气道炎症。基于此，本项目聚焦气道上皮细胞-Ba轴，进一步探讨OVA刺激上皮细胞表达TLR2、分泌TSLP招募Ba入肺脏，诱导后者经OX40/OX40L和CD40/CD40L通路，调节Th细胞分化并始动气道炎症的区域免疫特性，以此进一步阐释哮喘发生机制，为临床提供新的治疗靶点。

结项摘要

免疫调节异常是哮喘发病的重要机制。肺脏系非传统免疫器官，具有并形成独特免疫细胞及区域免疫特性。气道黏膜上皮为执行区域免疫主要场所，通过分泌胸腺基质淋巴生成素（TSLP）参与启动气道炎症。近年关注的嗜碱性粒细胞具有专职免疫细胞作用，过敏原激发后该细胞明显上调TSLP受体表达并受之调节。剔除嗜碱性粒细胞后OVA诱导的Th2免疫反应及气道炎症显著减轻，肺Th2型细胞因子水平降低。近期我们又发现哮喘期嗜碱性粒细胞能高表达OX40L和CD40。基于此，本项目聚焦气道上皮细胞-嗜碱性粒细胞轴，发现气道上皮细胞（AECs）在受到过敏原刺激后通过表达Toll样受体2（TLR2）,促进肺组织中趋化因子CCL2的增高，募集嗜碱性粒细胞入肺。TLR2-NF-κB/JNK信号通路参与AECs TSLP分泌，并通过TSLP-TSLPR轴活化树突状细胞（DCs）和嗜碱性粒细胞，并诱导后者经OX40-OX40L和CD40-CD40L通路诱发2型适应性免疫反应。我们还发现，血红素加氧酶-1（HO-1）可靶向结合NF-κB信号通路中p65信号分子、从而抑制TLR2-NF-κB通路，最终使Nod样受体蛋白（NLRP）3炎症小体表达下调，AECs TSLP分泌下降，Th2免疫反应减轻，该发现为临床防治提供新的理论依据和潜在干预靶点。