Role of Interleukin-1 in mediating epithelial-dendritic cell crosstalk in the lun

描述（由申请人提供）：哮喘是一种气道粘膜屏障的慢性炎症性疾病，在西方国家越来越常见。长期目标是找到预防和治疗这种疾病的新方法。气道树突状细胞（DC）和上皮细胞在过敏性致敏过程中起着至关重要的作用，并在控制哮喘典型的Th 2介导的过敏性炎症。屏障上皮细胞通过释放细胞因子影响DC的功能。最近的数据显示，将屋尘螨（HDM）过敏原施用到小鼠的气道诱导了几种DC激活细胞因子的增加，其中白细胞介素（IL）-1？是迄今发现的第一种细胞因子。此外，HDM驱动的过敏性炎症在缺乏IL-1受体（IL-1 R）的小鼠中没有发生。IL-1的产生和信号传导如何参与引起过敏性疾病。造血细胞和基质细胞都能产生IL-1 <$并对其产生应答。本研究的具体目的是阐明IL-1 <$/IL-1 R轴在吸入性过敏原致敏过程中介导上皮细胞和DC之间的串扰中的确切作用。在研究计划中，非常重视构建辐射嵌合小鼠，其中放射抗性基质细胞（包括上皮细胞，成纤维细胞，内皮细胞）或放射敏感性造血细胞（包括DC，单核细胞，多形核细胞和淋巴细胞）在IL-1/IL-1 R轴的关键途径中缺乏，如IL-1 R，NALP 3，ASC和caspase-1蛋白。在所有这些小鼠中，将研究轴的基质与造血缺陷对哮喘的显著特征如气道炎症、粘液分泌和支气管高反应性的影响。本文将对气道树突状细胞的功能进行详细的分析，重点关注树突状细胞在肺中的抗原摄取能力、动态扫描行为、迁移能力和T细胞极化能力。这些分析涉及使用最先进的流式细胞术和使用双光子显微镜对重要气管组织中DC的动态行为进行成像。更好地了解上皮细胞和DC的沟通方式可以使哮喘过敏致敏过程变得清晰，并最终为这种疾病开辟新的治疗和预防途径。来自该项目的知识也可能有助于解释在其他粘膜疾病如克罗恩病和溃疡性结肠炎中发生的上皮细胞和DC之间的相互作用。过敏性哮喘在过去50年中显著增加，对公共卫生构成重大负担，并影响许多人的日常生活。这个项目将有助于解开如何个人成为过敏时，暴露于屋尘螨过敏原。

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the mucosal barrier lining the airways that is seen increasingly in westernized countries. A long-term objective is to find novel ways of prevention and treatment of this disorder. Airway dendritic cells (DC) and epithelial cells play a crucial role in the process of allergic sensitization and in the control of Th2-mediated allergic inflammation typical of asthma. Barrier epithelial cells influence the function of DCs through release of cytokines. Recent data show that the administration of house dust mite (HDM) allergens to the airways of mice induced an increase in several DC-activating cytokines, amongst which interleukin (IL)-1¿, the first cytokine ever discovered. Moreover, HDM-driven allergic inflammation did not occur in mice lacking the IL-1 receptor (IL-1R). How exactly IL-1 production and signaling is involved in causing allergic disease. Both hematopoietic and stromal cells can produce IL1¿ and respond to it. The specific objective of this project is to unravel the precise contribution of the IL-1¿/IL-1R axis in mediating the crosstalk between epithelial cells and DCs during the process of allergic sensitization to inhaled allergens. In the research plan there is great emphasis on the construction of radiation chimeric mice in which either radioresistant stromal cells (including epithelial cells, fibroblasts, endothelial cells) or radiosensitive hematopoietic cells (including DCs, monocytes, polymorphonuclear cells and lymphocytes) are deficient in crucial pathways of the IL-1¿/IL-1R axis, such as the IL-1R, NALP3, ASC and caspase-1 proteins. In all these mice, the impact of stromal versus hematopoietic deficiency of the axis on salient features of asthma such as airway inflammation, secretion of mucus and bronchial hyperresponsiveness will be studied. A detailed analysis of the function of airway DCs will be performed, focusing on the antigen-uptake capacity, dynamic scanning behavior, migratory capacity and T cell polarizing capacity of DCs in the lungs. These analyses involve the use of cutting edge flow cytometry and imaging of the dynamic behavior of DCs in vital tracheal tissue using dual- photon microscopy. A better understanding of the way by which epithelial cells and DCs communicate could bring clarity in the process of allergic sensitization in asthma and could eventually unravel new therapeutic and preventive avenues for this disease. Knowledge originating from this project might also help explain interactions between epithelial cells and DC that occur in other mucosal disorders such as Crohn's disease and Ulcerative Colitis. Allergic asthma has increased significantly over the last 50 years, posing a significant burden to public health and affecting the daily life of many. This project will help unravel how individuals become allergic when exposed to house dust mite allergen.