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，在西方化国家越来越常见。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和哮喘典型的th2介导的过敏性炎症的控制中起关键作用。屏障上皮细胞通过释放细胞因子影响dc的功能。最近的数据表明，将屋尘螨（HDM）过敏原给予小鼠气道可诱导几种dc激活细胞因子的增加，其中包括白细胞介素(IL)-1¿，这是迄今发现的第一个细胞因子。此外，在缺乏IL-1受体（IL-1R）的小鼠中没有发生hdm驱动的过敏性炎症。IL-1的产生和信号传导究竟是如何引起过敏性疾病的？造血细胞和基质细胞都能产生il - 1并对其产生反应。该项目的具体目标是揭示IL-1¿/IL-1R轴在吸入过敏原的过敏致敏过程中介导上皮细胞和dc之间的串扰中的精确贡献。在研究计划中，重点是构建辐射嵌合小鼠，其中抗辐射的基质细胞（包括上皮细胞、成纤维细胞、内皮细胞）或对辐射敏感的造血细胞（包括dc、单核细胞、多形核细胞和淋巴细胞）缺乏IL-1 /IL-1R轴的关键通路，如IL-1R、NALP3、ASC和caspase-1蛋白。在所有这些小鼠中，将研究基质与造血轴缺乏对哮喘显著特征（如气道炎症、粘液分泌和支气管高反应性）的影响。我们将详细分析气道dc的功能，重点关注dc在肺部的抗原摄取能力、动态扫描行为、迁移能力和T细胞极化能力。这些分析包括使用尖端的流式细胞术和使用双光子显微镜对重要气管组织中DCs的动态行为进行成像。更好地了解上皮细胞和dc的交流方式可以使哮喘的过敏性致敏过程更加清晰，并最终揭示这种疾病的新的治疗和预防途径。来自这个项目的知识也可能有助于解释上皮细胞和DC之间的相互作用，这些相互作用发生在克罗恩病和溃疡性结肠炎等其他粘膜疾病中。过敏性哮喘在过去50年中显著增加，对公共卫生造成了重大负担，并影响了许多人的日常生活。这个项目将有助于解开如何个人变得过敏时，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.