Mechanisms of Particulate Matter Induced Dendritic Cell Activation

许多研究表明，暴露于空气中的颗粒物 (PM)和哮喘的症状然而，这种关联的机制仍然未知。 利用小鼠品系，我们已经证明，暴露于真实的世界颗粒物， 在某些品系的小鼠（A/J）中诱导过敏反应，而在另一些品系的小鼠（C3 H/HeJ）中不诱导过敏反应。我们的初步 研究表明，PM暴露可能通过改变树突状细胞而赋予哮喘症状的易感性， (DC)表型和功能。具体来说，我们已经作出了新的观察，PM改变了 免疫原性髓样DC与致耐受性浆细胞样DC募集到肺的相对比例 易感A/J小鼠。虽然AUB调节DC功能的机制尚不清楚，但我们的研究表明， 初步数据表明，以下假设：环境PM诱导过敏反应，通过 通过协同氧化剂和模式识别受体激活树突状细胞- 依赖性（PRRs）途径。为了验证这一假设，我们提出了以下目标：1）确定 PM诱导上皮细胞产生趋化因子和DC的分子机制 招募，我们将测试的假设，PM诱导上皮细胞趋化因子的生产和DC 通过氧化应激途径招募和成熟; 2）通过以下方法确定确切机制： PM在体外改变DC细胞表型、成熟和T细胞刺激能力， 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（DC亚群、共刺激分子表达、细胞因子 产生、刺激CD 4 +T细胞）在敏感和抗性鼠品系中使用以下的组合 方法（即药理学抑制剂，基因工程小鼠）;和3）为了确定 AUB激活的DC亚群对过敏性气道形成易感性的作用 在小鼠品系（A/J，C3 H）的体内反应中，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 的DC和随后的AUB诱导的过敏性表型的发展。再加上 其他项目的结果，本提案的结果将提供一个更好的了解如何 暴露于环境颗粒物质可加剧和/或诱发气道炎症， 呼吸系统疾病，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。

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.