Regulation of Macrophage Activation by House Dust Mite

屋尘螨对巨噬细胞激活的调节

• 批准号: 8670552
• 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/8670552
• 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; 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表现出增加过敏性鼻炎和哮喘的风险。与国土驻扎的人员相比，部署在波斯湾的士兵有发生过敏性鼻炎的风险的两倍，是患哮喘的风险的1.6倍。此外，12岁以后诊断出患有症状的哮喘是对军事入伍的排除批评。尽管尚未确定出现过敏性炎症疾病风险增加的原因，但被认为是最有可能的解释，暴露于高水平的灰尘和其他遗传颗粒。在伊拉克服役的数十名士兵中，发现无处不在的环境过敏原，房屋尘螨（HDM），被称为哮喘的主要影响。据估计，鼻炎和哮喘的50-80％是由于HDM引起的。但是，HDM诱导和加剧哮喘的机制尚未完全了解。 HDM和许多其他涉及的组件包含我们称为过敏原相关的分子模式（AAMP）的刺激结构，这些结构（AAMP）吸收和刺激了先天模式识别受体（PRR）。尽管其他人研究了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，巨噬细胞是先天性免疫系统中核心并在肺和气道中抽象中发现的细胞。 HDM刺激巨噬细胞诱导IFN-€的表达和几种具有替代激活的巨噬细胞（AAM）（包括几丁质酶家族成员）的特征，这些基因与过敏性疾病密切相关。这是，我们在该提案中的总体目标是表征HDM使用的先天免疫传感系统，该系统导致巨噬细胞分化的替代激活状态。对这一过程的理解在临床上很重要。人类哮喘患者的血液和气道中的几丁质蛋白数量增加，尤其是在哮喘加剧期间。此外，我们已经表明，AAM在小鼠模型中启动并扩大了哮喘的症状。要测试的中心假设是，在HDM中发现的AAMP阵列激活了先天信号通路，该途径在巨噬细胞中协同导致AAM基因的表达增强了过敏和哮喘。旨在检验这些假设的具体目的是1）确定HDM诱导的反应中细胞表面传感器的贡献，2）确定炎症体和IL-1家族成员在HDM诱导的效应中的作用，3）分析IFN-对HDM诱导的响应的贡献，并通过对HDM诱导的响应进行验证，以及4）对HDM的效应的效应，而HDM的效应是hDM的效应，则是hDM的效应。控制或哮喘退伍军人。这些实验将在体外通过刺激用HDM制备的巨噬细胞刺激巨噬细胞。我们还将分析HDM对源自PBMC的人类巨噬细胞的影响。重要的是，一旦我们确定了HDM诱导的对巨噬细胞在体外作用的影响所必需的先天传感器和信号传导途径，我们将使用HDM诱导的HDM诱导的哮喘的小鼠模型在体内分析传感器在巨噬细胞激活和过敏性肺部感染中的重要性。我们研究的预期结果是，它将描述由无处不在的环境过敏原HDM激活的信号传导途径。知识的增加将对退伍军人和国家有益，因为这些途径可能会导致确定控制HDM诱导的过敏性鼻炎和哮喘的新目标。