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）：过敏原是哮喘急性发作的最常见原因，导致气道平滑肌细胞炎症和收缩。过敏原会触发肺部各种细胞类型释放白细胞介素 (IL)-33。 IL-33 刺激 2 型先天淋巴细胞 (ILC2) 和辅助性 T 2 (Th2) 细胞分泌大量 IL-5 和 IL-13，它们是 Th2 炎症反应的重要介质。 IL-5 和 IL-13 与 IL-4 一起导致与哮喘相关的典型病理：气道高反应性、嗜酸性粒细胞炎症和粘液过度分泌。值得注意的是，在哮喘/过敏性气道炎症 (AAI) 的屋尘螨 (HDM) 或卵清蛋白 (OVA) 模型中，缺乏晚期糖基化终末产物 (RAGE) 受体的小鼠中不存在这些病理学发现。这些数据表明，RAGE（一种在肺部高表达的促炎性、多配体、免疫球蛋白样受体）对于过敏原诱导的哮喘 Th2 反应的发展是必需的。 RAGE 敲除 (KO) 和野生型 (WT) 小鼠均表现出响应 HDM 或 OVA 的 IL-4、免疫球蛋白 (Ig)-G 和 IgE 的正常增加，然而，只有 WT 小鼠表现出细胞因子 IL-5 的增加和IL-13。在没有 RAGE 的情况下，暴露于过敏原后无法产生 IL-5 和 IL-13 反应可能是由于适应性免疫系统（Th2 细胞）、先天免疫系统（ILC2）或两者的缺陷所致。此外，Th2细胞因子产生的这些缺陷可能是由于RAGE KO小鼠无法增加IL-33水平所致，与用HDM治疗的WT小鼠相比，IL-33水平在RAGE KO小鼠中也异常没有增加。本研究旨在研究过敏原暴露后控制 Th2 反应诱导的上游信号事件。首先，流式细胞术将用于确定 RAGE 信号传导的缺失是否会损害 Th2 细胞、ILC2 或两者中的细胞募集和/或细胞因子产生。接下来，细胞培养研究将确定 RAGE 信号传导是否通过促进 IL-33 分泌和/或通过 Th2 细胞、ILC2 或两者上的直接 RAGE 信号传导间接增加 IL-5 和 IL-13 的产生。了解 RAGE 信号丢失预防哮喘发病机制的机制可能有助于发现治疗哮喘或预防过敏原引起的疾病恶化的新治疗靶点。