Inhaled Mine-Site Derived Metal Particulate Matter Drives Pulmonary and Systemic Immune Dysregulation

项目总结/摘要 吸入矿区粉尘是人类接触金属混合物的一个相关途径， 在四个地区，居住在废弃铀矿和硬岩矿场附近的部落社区的健康问题， 美国西南部的一个角落地区。新墨西哥州大学的金属暴露和 西南部部落土地的毒性评估（UNM金属）团队已经证明， 纳瓦霍民族的个体对金属混合物的依赖与免疫失调的生物标志物有关 居住在废弃铀矿附近与抗核自身抗体水平相关。 该地区也是间质性肺病、矽肺和其他慢性呼吸道疾病的地理中心。 这些疾病与环境暴露和系统性自身免疫有关。目前尚不清楚 吸入的富含金属的颗粒物如何驱动肺外免疫失调。此外该 不同单个金属的贡献（例如，铀、钒和铁）驱动这些免疫介导的 变化尚待明确界定。BioProject - Lung（BP Lung）专注于研究 金属介导的免疫失调，无论是局部在肺部，以及全身吸入后 暴露在富含金属的微粒中因此，我们的主要目标是确定这些变化如何有助于 肺损伤和自身免疫发展。因为金属会在骨头里堆积我们有证据 骨髓微环境中的炎症变化反映了颗粒物引起的肺反应， 暴露，第二个目标是研究骨髓龛和肺之间的串扰， 金属颗粒介导的免疫功能障碍我们的核心假设是铀和富含铀的 颗粒混合物通过以下途径驱动肺部和全身免疫失调和自身免疫 NETosis过度活跃，部分通过在骨髓龛中引发中性粒细胞NETosis。在目标1中，我们 利用一种新的高内涵成像，基于机器学习的单细胞平台来研究个体如何 金属单独或与其他金属和矿物质组合有助于氧化应激、炎症和 使用人体外模型的NETosis。在目标2中，我们将使用自身免疫易感小鼠模型来确定 中性粒细胞和NETosis在气载金属介导的肺和全身免疫发展中的作用 使用几种已建立的NETosis抑制剂来治疗失调和自身免疫发展。在目标3中，我们 将目标1和目标2中的机械发现转化为研究空气中金属 来自拉古纳普韦布洛合作社区的个体暴露和气道炎症介质， 与BP Comm和CEC合作。这项工作是创新和重要的，因为它利用了国家的， 艺术工具，以提供对中性粒细胞和NETosis作为机制靶点的作用的详细理解， 金属颗粒暴露后全身免疫失调的驱动因素以及 骨髓小生境和肺有助于这些病理。

Project Summary/Abstract Inhalation of mine site dust is a relevant route of human exposure to metal mixtures that poses a significant health concern for tribal communities living near abandoned uranium and hard rock mine sites in the four- corners region of the Southwestern United States. The University of New Mexico's Metals Exposure and Toxicity Assessment on Tribal Land in the Southwest (UNM METALS) team has demonstrated that exposure of individuals in the Navajo Nation to metal mixtures is associated with biomarkers of immune dysregulation and living in close proximity to abandoned uranium mines correlates with levels of anti-nuclear autoantibodies. This region is also a geographic epicenter for interstitial lung disease, silicosis and other chronic respiratory disorders, which are linked to environmental exposures and systemic autoimmunity. It is currently not known how inhaled metal-rich particulates drive extrapulmonary immunological dysregulation. In addition, the contribution of different individual metals (e.g., uranium, vanadium, and iron) in driving these immune-mediated changes has yet to be clearly defined. BioProject – Lung (BP Lung) focuses on investigating mechanisms of metal-mediated immune dysregulation both locally in the lungs, as well as systemically following inhalation exposure to metal-rich particulates. Thus, our main objective is to determine how these changes contribute to pulmonary injury and autoimmune development. Because metals accumulate in bone and we have evidence that inflammatory changes in the bone marrow niche mirror pulmonary responses following particulate exposure, a second goal is to investigate crosstalk between the bone marrow niche and the lungs contributing to metal particulate-mediated immune dysfunction. Our central hypothesis is that uranium and uranium-rich particulate mixtures drive pulmonary and systemic immune dysregulation and autoimmunity through hyperactive NETosis, in part by priming neutrophils for NETosis in the bone marrow niche. In Aim 1, we will utilize a novel high content imaging, machine learning-based single cell platform to investigate how individual metals alone or in combination with other metals and minerals contribute to oxidative stress, inflammation, and NETosis using human, in vitro models. In Aim 2, we will use an autoimmune prone mouse model to determine the role of neutrophils and NETosis in the development of airborne metal-mediated lung and systemic immune dysregulation and autoimmune development using several established NETosis inhibitors. In Aim 3, we will translate our mechanistic findings from Aims 1 and 2 to investigate associations between airborne metal exposure and airway inflammatory mediators in individuals from Laguna Pueblo partnering community in collaboration with BP Comm and CEC. This work is innovative and significant because it utilizes state-of-the art tools to provide detailed understanding of the effect of neutrophils and NETosis as mechanistic targets and driver of systemic immune dysregulation following metal particulate exposure and how crosstalk between the bone marrow niche and the lungs contribute to these pathologies.