Regulation of Macrophage Activation by House Dust Mite

屋尘螨对巨噬细胞激活的调节

• 批准号: 9898273
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898273
• 关键词: 12 year old; Actins; Adoptive Transfer; Allergens; Allergic; Allergic Disease; Allergic rhinitis; Asthma; Autophagocytosis; Autophagosome; Blood; CASP1 gene; CASP2 gene; Caspase; Cell surface; Cells; Characteristics; Chemotaxis; Chitinase; Clinical; Confocal Microscopy; Data; Dendritic Cells; Diagnosis; Disease; Dust; Epithelial Cells; Exclusion Criteria; Exposure to; Extrinsic asthma; Family member; Flow Cytometry; Funding; Gene Expression; Genes; Goals; House Dust Mite Allergens; Human; Human Resources; Hypersensitivity; Image; In Vitro; Inflammation; Inflammatory; Inhalation; Innate Immune System; Interferons; Interleukin-1 beta; Iraq; Knowledge; Label; Lipids; Lung; Lung Inflammation; Macrophage Activation; Measures; Military Personnel; Mite Controls; Molecular; Monitor; Morphology; Mus; Names; Outcome; Particulate; Partner in relationship; Pathway interactions; Pattern; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Persian Gulf; Phagocytosis; Phagolysosome; Phenotype; Process; Proteins; Pyroglyphidae; Regulation; Research; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis; Risk; Role; Sampling; Shapes; Signal Pathway; Soldier; Son; Stream; Structure; Surface; Symptoms; System; TLR4 gene; Testing; Time; United States; Vesicle; Veterans; Western Blotting; asthma exacerbation; asthmatic; cell motility; design; environmental allergen; enzyme activity; experimental study; in vivo; knock-down; macrophage; man; migration; mouse model; novel; particle; protein expression; response; trafficking; vif Genes

United States (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 criterion for military enlistment. While the rea- son for the increased risk for allergic inflammatory 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-as- sociated 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 the macrophage (Mφ) - a cell that is central in the innate immune system and found in abundance in the lungs and airways. HDM stimulates Mφs to induce the expression of IFNβ and several genes that are char- acteristic of alternatively-activated Mφs (also termed M2 Mφs), including chitinase family members. We identi- fied a novel pathway between the induction of IFNβ and caspase 11 that controls chitinase gene expression and Mφ morphology without inducing high levels of IL-1β or pyroptosis. Furthermore, our preliminary data show that: (i) HDM stimulates an increase in caspase 11 protein and enzyme activity in a TLR4-independent manner; (ii) caspase 11 is required for chitinase gene expression and optimal IFNβ induced by HDM in vitro; (iii) HDM induces a dramatic change in Mφ size and shape with pronounced changes in actin dynamics, {a response replicated by dust samples from Camp Victory, Iraq; (iv) HDM stimulates expression of protein spe- cies indicative of autophagy-related processes, such as LC-3 lipidation, without degradative flux;} and (v) we observed similar HDM-induced changes in human primary Mφs. Thus, our overall goal in this renewal proposal is to characterize the mechanism by which the non-canonical caspase 11 pathway controls Mφ phenotype and thus HDM-induced asthma. An understanding of this process is clinically important since human asthmatics have elevated numbers of M2, as well as increased amounts of chitinase proteins in their blood and airways- especially during asthma exacerbations. Furthermore, we have shown that M2 initiate and amplify the symp- toms of asthma in a mouse model. The central hypothesis to be tested is that the caspase 11 pathway regulates the expression of a sub- set of M2 genes in Mφs and controls Mφ morphology and migration by regulating actin dynamics critical for phagolysome and autophagosome fusion, thereby enhancing allergy and asthma. The specific aims designed to test this hypothesis are: 1) to characterize the role of caspase 11 in regulating HDM-induced changes in Mφ phenotype and allergic lung inflammation, 2) to delineate the contribution of caspase 11 and autophagic ma- chinery to the regulation of actin dynamics and Mφ motility induced by HDM, and 3) to validate HDM-induced responses in human Mφs and {compare responses in Mφs from from asthmatics and control subjects.} 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 M2 genes and Mφ function. This increase in knowledge will have benefit for Veterans and the nation because these pathways will likely lead to the identifi- cation of new targets for the control of HDM-induced allergic rhinitis and asthma.

在伊拉克服役的美国（美国）士兵表明，过敏性鼻炎和 哮喘;与 国土驻扎人员，是患哮喘的风险的1.6倍。此外，诊断 12岁以后患有症状的哮喘是军事入伍的排除标准。而 尚未建立过敏性炎症性疾病风险增加的儿子，暴露于高水平 尘埃和其他继承的颗粒被认为是最有可能的解释。无处不在的环境 过敏原，房屋尘螨（HDM），在伊拉克服役的数十名士兵中发现了高水平 成为哮喘的主要诱导剂。据估计，在50-80％的鼻炎和哮喘之间 HDM。但是，HDM诱导和加剧哮喘的机制尚未完全了解。 HDM和许多其他吸入组件包含我们称为过敏原的模拟结构 社会化的分子模式（AAMPS），它们参与和刺激先天模式识别受体（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（M或 肺和气道。 HDM刺激MφS诱导IFNβ的表达和几种char-的基因 替代激活的MφS（也称为M2mφs）的杂质，包括几丁质酶家族成员。我们确定 - 罚款在控制几丁质酶基因表达的IFNβ和caspase 11之间的新途径 和Mφ形态，没有诱导高水平的IL-1β或凋亡。此外，我们的初步数据 证明：（i）HDM刺激caspase 11蛋白和酶活性的增加 方式; （ii）caspase 11是粒素酶基因表达和HDM在体外诱导的最佳IFNβ所必需的； （iii）HDM诱导Mφ大小和形状的急剧变化，并在肌动蛋白动力学中发生明显变化，{a 伊拉克营地胜利的尘埃样本复制了回应； （iv）HDM刺激蛋白质Spe-的表达 指示自噬相关过程的CIE，例如LC-3脂质，没有降解通量；}和（v）我们 观察到类似的HDM诱导的人类原发性Mφ的变化。这，我们在此续签建议中的总体目标 是为了表征非经典caspase 11途径控制Mφ表型和 因此，HDM诱导的哮喘。对这一过程的理解在临床上很重要，因为人类哮喘患者 M2的数量升高，血液和气道中的几丁质蛋白量增加 - 尤其是在哮喘加剧期间。此外，我们已经表明M2启动并扩大了Symp- 小鼠模型中的哮喘toms。 要测试的中心假设是caspase 11途径调节了亚的表达 MφS中的M2基因集并通过控制肌动蛋白动力学至关重要地控制Mφ形态和迁移 吞噬体和自噬体融合，从而增强过敏和哮喘。设计的特定目的 检验该假设是：1）表征caspase 11在调节HDM诱导的Mφ变化中的作用 表型和过敏性肺注射，2）描述caspase 11和自噬的贡献 Chinary对HDM诱导的肌动蛋白动力学和Mφ运动的调节，以及3）验证HDM诱导的 人类MφS中的响应和{比较来自哮喘和控制对象的MφS中的响应。} 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驱动M2基因和Mφ功能的表达。这增加了 知识将对退伍军人和国家有利，因为这些途径可能会导致身份证明 - 控制HDM诱导的过敏性鼻炎和哮喘的新靶标。