RAGE as an upstream activator of the Th2 inflammatory immune response in asthma

RAGE 作为哮喘 Th2 炎症免疫反应的上游激活剂

基本信息

批准号：
8714285
负责人：
Elizabeth A Oczypok
金额：
$ 4.76万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714285
关键词：
Acute Adrenal Cortex Hormones Advanced Glycosylation End Products Affect Allergens Asthma Blocking Antibodies Breathing Bronchoconstriction Bronchodilator Agents Cell Count Cell Culture Techniques Cells Data Defect Dendritic Cells Development Disease Effector Cell Enzyme-Linked Immunosorbent Assay Event Exposure to Flow Cytometry Goblet Cells Hyperplasia IgE Immune response Immune system Immunoglobulin G Immunoglobulins Inflammation Inflammatory Inflammatory Response Interleukin-13 Interleukin-4 Interleukin-5 Interleukins Investigation Knock-out Knockout Mice Lead Ligands Lung Lymphoid Cell Measures Mediator of activation protein Modeling Molecular Morbidity - disease rate Mucous body substance Mus Ovalbumin Parasites Pathogenesis Pathology Patients Play Prevention Process Production Pyroglyphidae Resistance Role Secondary to Signal Transduction Smooth Muscle Myocytes Structure of parenchyma of lung Surface T-Lymphocyte Testing Time Western Blotting Wild Type Mouse airway hyperresponsiveness allergic airway inflammation asthma prevention asthmatic airway cell type constriction cytokine environmental allergen environmental particulate eosinophilic inflammation macrophage new therapeutic target novel novel therapeutics prevent public health relevance receptor respiratory smooth muscle response

项目摘要

DESCRIPTION (provided by applicant): Allergens are the most common cause of acute asthma exacerbations, leading to inflammation and constriction of airway smooth muscle cells. Allergens trigger the release of interleukin(IL)-33 from various cell types in the lung. IL-33 stimulates both type 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) cells to secrete large amounts of IL-5 and IL-13, which are important mediators of the Th2 inflammatory response. IL-5 and IL-13, along with IL-4, are responsible for the classic pathology associated with asthma: airway hyper-responsiveness, eosinophilic inflammation, and mucus hyper-secretion. Notably, these pathological findings are not present in mice lacking the receptor for advanced glycation end products (RAGE) in the house dust mite (HDM) or ovalbumin (OVA) models of asthma/allergic airway inflammation(AAI). These data suggest that RAGE, a pro- inflammatory, multi-ligand, immunoglobulin-like receptor that is highly expressed in the lung, is necessary for the development of an allergen-induced asthmatic Th2 response. Both RAGE knockout (KO) and wild-type (WT) mice demonstrate normal increases in IL-4, immunoglobulin(Ig)-G, and IgE in response to HDM or OVA, however, only WT mice demonstrate increases in cytokines IL-5 and IL-13. The inability to mount an IL-5 and IL-13 response after allergen exposure in the absence of RAGE could be due to defects in the adaptive immune system (Th2 cells), the innate immune system (ILC2s), or both. Furthermore, these deficits in Th2 cytokine production may be secondary to an inability of RAGE KO mice to increase levels of IL-33, which was also abnormally not increased in RAGE KO mice as compared to WT mice treated with HDM. This investigation seeks to study the upstream signaling events that control the induction of the Th2 response following allergen exposure. First, flow cytometry will be use to determine if absence of RAGE signaling impairs cellular recruitment and/or cytokine production in Th2 cells, ILC2s, or both. Next, cell culture studies will determine if RAGE signaling increases IL-5 and IL-13 production indirectly by promoting IL-33 secretion and/or through direct RAGE signaling on Th2 cells, ILC2s, or both. Understanding the mechanisms by which loss of RAGE signaling prevents asthma pathogenesis may lead to the discovery of new therapeutic targets for the treatment of asthma or the prevention of allergen-induced exacerbations of the disease.

描述（由申请人提供）：过敏原是急性哮喘加重的最常见原因，导致气道平滑肌细胞的炎症和收缩。过敏原触发肺中各种细胞类型的白介素（IL）-33的释放。 IL-33刺激2型先天性淋巴样细胞（ILC2S）和T-辅助2（Th2）细胞分泌大量IL-5和IL-13，这是Th2炎症反应的重要介体。 IL-5和IL-13以及IL-4造成了与哮喘相关的经典病理：气道高反应性，嗜酸性炎症和粘液过度分泌。值得注意的是，这些病理发现并不存在于缺乏哮喘/过敏性气道炎症（AAI）的房屋粉尘螨（HDM）或卵脂蛋白（OVA）模型的小鼠中。这些数据表明，在肺中高度表达的狂热，一种炎症，多配体，类似免疫球蛋白样受体，对于发展过敏原诱导的哮喘TH2反应是必不可少的。 RAGE敲除（KO）和野生型（WT）小鼠均表现出对HDM或OVA的IL-4，免疫球蛋白（Ig）-G和IgE的正常增加，但是，只有WT小鼠在WT小鼠中显示出细胞因子IL-5和IL-5和IL-13的增加。在没有愤怒的情况下过敏原暴露后无法安装IL-5和IL-13反应可能是由于自适应免疫系统（TH2细胞），先天免疫系统（ILC2S）或两者兼而有之。此外，Th2细胞因子产生的这些缺陷可能是rage KO小鼠无法提高IL-33的水平的继发性，而与用HDM处理的WT小鼠相比，RAGE KO小鼠的IL-33水平也异常增加。该研究旨在研究过敏原暴露后控制Th2反应的诱导的上游信号事件。首先，将使用流式细胞仪来确定不存在愤怒信号会损害Th2细胞，ILC2或两者兼而有之的细胞募集和/或细胞因子的产生。接下来，细胞培养研究将通过促进IL-33分泌和/或通过Th2细胞，ILC2S或两者兼而有之，通过促进IL-33分泌和/或直接rage信号来确定愤怒信号传导是否会间接增加IL-5和IL-13产生。了解愤怒信号丧失阻止哮喘发病机理的机制可能导致发现新的治疗靶标，以治疗哮喘或预防过敏原诱导的疾病加重。