Mechanisms of Particulate Matter Induced Dendritic Cell Activation

颗粒物诱导树突状细胞激活的机制

• 批准号: 8294888
• 负责人: Marsha Wills-Karp
• 金额: $ 53.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294888
• 关键词: A/J Mouse; Adoptive Transfer; Air; Airborne Particulate Matter; Allergic; Antigen Presentation; Antigens; Aromatic Hydrocarbons; Asthma; Attention; Baltimore; Breathing; CD4 Positive T Lymphocytes; Cell physiology; Cells; Child; Childhood Asthma; Chronic; Complex Mixtures; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease susceptibility; Endotoxins; Environment; Environmental Risk Factor; Epidemiology; Epithelial Cells; Epithelium; Exposure to; Extrinsic asthma; Fungal Components; Genetic; Genetically Engineered Mouse; Goals; Health; Human; ITGAM gene; ITGAX gene; In Vitro; Inbreeding; Individual; Intervention; Life; Lung; Mediating; Metals; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Myelogenous; Onset of illness; Oxidants; Oxidative Stress; Oxidative Stress Pathway; Particulate Matter; Pathway interactions; Pattern recognition receptor; Phenotype; Play; Predisposition; Prevalence; Process; Production; Recruitment Activity; Regulation; Relative (related person); Research Design; Research Personnel; Resistance; Role; Signal Transduction; Societies; Source; Stress; Surface; Symptoms; T cell differentiation; T-Lymphocyte; Testing; Translations; airway hyperresponsiveness; airway inflammation; allergic response; base; chemokine; clinical application; cytokine; dectin 1; environmental particulate; eosinophilic inflammation; immunogenic; immunogenicity; in vivo; inhibitor/antagonist; inner city; insight; novel; pollutant; programs; respiratory; response

Numerous studies have shown a strong association between exposure to airborne particulate matter (PM) and indicators of asthma. However, the mechanisms underlying this association remain unknown. Utilizing murine strains of mice, we have demonstrated that exposure to real world particulate matter induces allergic responses in some strains (A/J) of mice, while not in others (C3H/HeJ). Our preliminary studies suggest that PM exposure may confer susceptibility to asthma symptoms by altering dendritic cell (DC) phenotype and function. Specifically, we have made the novel observation that PM alters the relative proportion of immunogenic myeloid DC to tolerogenic plasmacytoid DC recruited to the lungs of susceptible A/J mice. Although the mechanisms by which AUB regulates DC function are unknown, our preliminary data suggests the following hypothesis: that ambient PM induces the allergic response via activation of dendritic cells through synergistic oxidant and pattern recognition receptor- dependent (PRRs) pathways. To test this hypothesis, we propose the following aims: 1) To determine the molecular mechanisms by which PM-induces epithelial cell chemokine production and DC recruitment, we will test the hypothesis that PM induces epithelial cell chemokine production and DC recruitment and maturation via oxidative stress pathways; 2) To determine the exact mechanisms by which PM alters DC cell phenotype, maturation and T cell stimulatory ability in vitro, we will evaluate the contribution of oxidative stress and pattern recognition receptor pathways (TLRs and dectin-1) to PM- induced alterations in DC phenotype (DC subset, costimulatory molecule expression, cytokine production, stimulation of CD4+T cells) in susceptible and resistant murine strains using a combination of approaches (i.e. pharmacological inhibitors, genetically engineered mice); and 3) To determine the contribution of AUB-activated DC subsets to susceptibility to the development of allergic airway responses in murine strains (A/J, C3H) in vivo, we will test the hypothesis that genetic differences in activation of oxidant and/or pattern recognition receptors (TLRs, dectin-1) contribute to altered activation of DC and subsequent development of the AUB-induced allergic phenotype. Taken together with the results of the other projects, the results of this proposal will provide a better understanding of how exposures to environmental particulate matter may exacerbate and/or induce airway inflammation and respiratory morbidity with the ultimate goal of translation of information into clinical applications or intervention strategies that can be used to reduce the morbidity of childhood asthma.

大量研究表明，暴露于空气中的颗粒物之间存在密切关系 (PM) 和哮喘指标。然而，这种关联背后的机制仍然未知。 利用小鼠品系，我们已经证明接触现实世界的颗粒物 在某些品系（A/J）小鼠中引起过敏反应，而在其他品系（C3H/HeJ）中则不引起过敏反应。我们的初步 研究表明，PM 暴露可能通过改变树突状细胞而导致对哮喘症状的易感性 (DC)表型和功能。具体来说，我们进行了新的观察，即 PM 改变了 招募到肺部的免疫原性髓样 DC 与耐受性浆细胞样 DC 的相对比例 易感A/J小鼠。尽管 AUB 调节 DC 功能的机制尚不清楚，但我们的研究 初步数据表明以下假设：环境 PM 通过以下途径诱发过敏反应： 通过协同氧化剂和模式识别受体激活树突状细胞- 依赖（PRR）途径。为了检验这一假设，我们提出以下目标：1）确定 PM诱导上皮细胞趋化因子产生和DC的分子机制 招募，我们将测试 PM 诱导上皮细胞趋化因子产生和 DC 的假设 通过氧化应激途径招募和成熟； 2）确定确切的机制 PM 在体外改变 DC 细胞表型、成熟和 T 细胞刺激能力，我们将评估 氧化应激和模式识别受体途径（TLR 和 dectin-1）对 PM-的贡献 诱导 DC 表型的改变（DC 子集、共刺激分子表达、细胞因子 使用以下组合在易感和耐药小鼠品系中产生、刺激 CD4+T 细胞） 方法（即药物抑制剂、基因工程小鼠）； 3) 确定 AUB 激活的 DC 亚群对过敏性气道发展的易感性的贡献 为了研究小鼠品系（A/J、C3H）体内的反应，我们将检验以下假设： 氧化剂和/或模式识别受体（TLR、dectin-1）的激活有助于改变激活 DC 的形成以及 AUB 诱导的过敏表型的后续发展。与 与其他项目的结果相比，本提案的结果将有助于更好地理解如何 暴露于环境颗粒物可能会加剧和/或诱发气道炎症和 呼吸系统疾病的最终目标是将信息转化为临床应用或 可用于降低儿童哮喘发病率的干预策略。