Regulation of Macrophage Activation by House Dust Mite

屋尘螨对巨噬细胞激活的调节

• 批准号: 8541976
• 负责人: Achsah D. Keegan
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541976
• 关键词: 12 year old; Acute; Agonist; Allergens; Allergic; Allergic Disease; Allergic inflammation; Allergic rhinitis; Asthma; Blood; Breathing; C Type Lectin Receptors; Caspase-1; Cell Line; Cell surface; Cells; Characteristics; Chitinase; Dendritic Cells; Diagnosis; Disease; Dust; Epithelial Cells; Exclusion; Exposure to; Extrinsic asthma; Family; Family member; Gene Expression; Genes; Goals; Human; Human Resources; Hypersensitivity; Immune; Immune system; In Vitro; Infection; Interferons; Interleukin-1; Interleukin-18; Iraq; Knowledge; Lead; Lung; Lung Inflammation; Macrophage Activation; Military Personnel; Mite Controls; Molecular; Molecular Profiling; Mus; Outcome; PAR-2 Receptor; Particulate; Pathway interactions; Pattern; Pattern recognition receptor; Peptides; Peripheral Blood Mononuclear Cell; Persian Gulf; Play; Process; Proteins; Pyroglyphidae; Regulation; Reporting; Research; Research Project Grants; Respiratory syncytial virus; Rhinitis; Risk; Role; STAT1 gene; Signal Pathway; Soldier; Structure; Symptoms; System; TLR2 gene; Testing; Time; United States; Veterans; cell type; design; environmental allergen; gene induction; in vivo; inhibitor/antagonist; macrophage; monocyte; mouse model; novel; particle; public health relevance; receptor; research study; response; sensor; toll-like receptor 4

DESCRIPTION (provided by applicant): US soldiers who have served in Iraq show an increased risk for allergic rhinitis and asthma. Soldiers deployed in the Persian Gulf had twice the risk of developing allergic rhinitis as compared to homeland stationed personnel and 1.6 times the risk of developing asthma. Furthermore, the diagnosis of asthma with symptoms after the age of 12 years is an exclusion critierion for military enlistment. While the reason for the increased risk for allergic inflammatoy diseases has not been established, exposure to high levels of dust and other inhaled particles is thought to be the most likely explanation. The ubiquitous environmental allergen, house dust mite (HDM), was found in high levels in the tents of soldiers serving in Iraq and is known to be a major inducer of asthma. It has been estimated that between 50-80% of rhinitis and asthma is due to HDM; however, the mechanisms by which HDM induces and exacerbates asthma are not fully understood. HDM and many other inhaled particulates contain stimulatory structures we have termed allergen- associated molecular patterns (AAMPs) that engage and stimulate innate pattern recognition receptors (PRR). While others have studied the effects of HDM on epithelial and dendritic cells, we have found that HDM directly activates macrophages, a cell that is central in the innate immune system and found in abundance in the lungs and airways. HDM stimulates macrophages to induce the expression of IFN-¿ and several genes that are characteristic of alternatively activated macrophages (AAM), including chitinase family members, that are strongly associated with allergic disease. Thus, our overall goal in this proposal is to characterize the innate immune sensing systems utilized by HDM that lead to an alternatively activated state of macrophage differentiation. An understanding of this process is clinically important; human asthmatics have elevated numbers of AAM and increased amounts of chitinase proteins in their blood and airways, especially during asthma exacerbations. Furthermore, we have shown that AAM initiate and amplify the symptoms of asthma in a mouse model. The central hypothesis to be tested is that the array of AAMPs found in HDM activate innate signaling pathways that coordinately lead to the expression of AAM genes in macrophages enhancing allergy and asthma. The specific aims designed to test these hypotheses are 1) to determine the contribution of cell surface sensors in HDM-induced responses, 2) to determine the role of the inflammasome and IL-1 family members in HDM-induced effects, 3) to analyze the contribution of IFN-¿ to the HDM-induced responses, and 4) to validate the effect of HDM on macrophages by comparing responses in human macrophages isolated from controls or asthmatic veterans. These experiments will be performed in vitro by stimulating macrophages prepared from wild type and gene deficient mice with HDM. We will also analyze the effects of HDM on human macrophages derived from PBMC. Importantly, once we identify an innate sensor and signaling pathway that is necessary for HDM-induced effects on macrophages in vitro, we will analyze the importance of the sensor in macrophage activation and allergic lung inflammation in vivo using a mouse model of HDM-induced asthma. The anticipated outcome of our research is that it will delineate the signaling pathways activated by the ubiquitous environmental allergen HDM that drive expression of AAM genes. This increase in knowledge will have benefit for veterans and the nation because these pathways will likely lead to the identification of new targets for the control of HDM-induced allergic rhinitis and asthma.

描述（由申请人提供）： 曾在伊拉克服役的美国士兵患过敏性鼻炎和哮喘的风险增加，部署在波斯湾的士兵患过敏性鼻炎的风险是驻扎在本土的士兵的两倍，患哮喘的风险是其 1.6 倍。 12 岁后出现哮喘症状是入伍的排除标准，虽然过敏性炎症疾病风险增加的原因尚未确定，但人们认为接触高浓度的灰尘和其他吸入颗粒。最可能的解释是，在伊拉克服役的士兵的帐篷中发现了高含量的室内尘螨（HDM），据估计，它是哮喘的主要诱因。 -80% 的鼻炎和哮喘是由 HDM 引起的；然而，HDM 诱发和恶化哮喘的机制尚不完全清楚。 HDM 和许多其他吸入颗粒物都含有我们所说的刺激结构。虽然其他人研究了 HDM 对上皮细胞和树突状细胞的影响，但我们发现 HDM 直接激活巨噬细胞，巨噬细胞是免疫系统的核心细胞。 HDM 大量存在于先天免疫系统中，可刺激巨噬细胞诱导 IFN-¿ 的表达。以及替代激活巨噬细胞 (AAM) 的几个特征基因，包括几丁质酶家族成员，它们与过敏性疾病密切相关。因此，我们在本提案中的总体目标是表征 HDM 所利用的导致过敏性疾病的先天免疫传感系统。了解这一过程在临床上很重要；人类哮喘患者的血液和气道中 AAM 数量和几丁质酶蛋白含量增加，尤其是在哮喘恶化期间。 AAM 在小鼠模型中引发并放大哮喘症状 要测试的中心假设是，HDM 中发现的一系列 AAMP 激活先天信号通路，协调导致巨噬细胞中 AAM 基因的表达，从而增强过敏和哮喘。测试这些假设的目的是 1) 确定细胞表面传感器在 HDM 诱导的反应中的贡献，2) 确定炎性体和 IL-1 家族成员在 HDM 诱导的效应中的作用，3)分析 IFN-¿ 的贡献4) 通过比较从对照或哮喘退伍军人中分离出的人类巨噬细胞的反应来验证 HDM 对巨噬细胞的影响。这些实验将通过刺激从野生型和基因缺陷小鼠制备的巨噬细胞来进行。 HDM。我们还将分析 HDM 对 PBMC 衍生的人巨噬细胞的影响。重要的是，一旦我们确定了 HDM 诱导的体外巨噬细胞影响所必需的先天传感器和信号通路，我们将分析 HDM 对巨噬细胞的影响。使用 HDM 诱发哮喘的小鼠模型，我们研究了传感器在体内巨噬细胞激活和过敏性肺部炎症中的重要性，我们研究的预期结果是，它将描绘出由普遍存在的环境过敏原 HDM 激活的信号通路，驱动 AAM 基因的表达。知识的增加将为退伍军人和国家带来好处，因为这些途径可能会导致确定控制 HDM 引起的过敏性鼻炎和哮喘的新目标。