Role of alveolar macrophages in particulate matter-induced cardiopulmonary disease

颗粒物(PM)空气污染是一个全球性的环境健康问题，导致370万人早产 每年的死亡人数，占全球所有死亡人数的6.7%。这些死亡在很大程度上是由于急性呼吸道感染增加 包括肺炎在内的心肺疾病。虽然其机制尚不完全清楚，但肺泡 巨噬细胞(AM)驱动的肺部炎症在PM引起的健康效应中起着重要作用。为了进一步 以公正的方式探索潜在的机制，我们在暴露于PM的AM中进行了RNAseq在……里面 除了NF-κB靶基因(如IL-6)外，我们还发现免疫反应基因1(Irg1)是排名前10位的基因之一 由PM引发IRG1编码乌头酸脱羧酶1(Acod1)，这是一种线粒体酶，催化 衣康酸的合成。我们发现PM诱导的IRG1表达发生得较晚，在IL6和IL6表达之后 其他细胞因子。随着IRG1蛋白的表达，IL6的表达下降。衣康酸治疗AM的疗效观察 减少PM诱导的IL6，而IRG1的缺失具有相反的作用，并进一步增加PM诱导的IL6 表情。PM诱导AM中独特的代谢重新编程，其特征是糖酵解增加和 线粒体呼吸，这与内毒素(减少呼吸)的作用不同。PM也被诱导 线粒体ROS(MRO)从络合物I(CI)通过反向电子传输(RET)。重要的是，我们发现 PM诱导的IL6表达既需要呼吸增加，也需要RET驱动的MRO。依他康酸抑制药 PM通过抑制琥珀酸诱导线粒体呼吸、RET和由此产生的MRO增加 肺泡巨噬细胞脱氢酶(SDH)(CII)。PM或衣康酸治疗可减少炎症反应(IL6和 抗病毒反应基因)，提示PM通过IRG1/衣康酸/SDH抑制 可能会损害对病原体的炎症反应。根据这些初步数据，我们假设PM首先 增加炎症反应所需的线粒体呼吸、RET和MRO， 其次是IRG1/衣康酸的晚期表达，通过抑制SDH，减少线粒体 呼吸、RET、MROS和抑制炎症反应导致反应受损 病原体。我们将在三个具体目标上检验我们的假设。在目标1中，我们将确定如何增加 线粒体呼吸和IRG1/衣康酸调节PM诱导的代谢变化和转录 AM中的响应。在目标2中，我们将确定IRG1/衣康酸是否抑制PM诱导的转录 通过抑制反向电子传递和MROS来做出反应。在目标3中，我们将确定PM是否导致 IRG1/衣康酸削弱了对后续感染的炎症反应。在这第一项研究中，探索了 PM对AM代谢的影响--代谢变化与转录变化的同步分析 数据将为我们提供有关代谢如何产生PM诱导的生物效应的重要知识 我们对PM诱导的IRG1/衣康酸如何抑制对病原体的炎症反应的研究有 有可能为预防PM暴露引起的肺炎提供新的治疗靶点。

Particulate matter (PM) air pollution is a global environmental health problem that causes 3.7 million premature deaths annually, representing 6.7% of all deaths worldwide. These deaths are largely due to increased acute cardiopulmonary disease including pneumonia. While the mechanisms are not completely understood, alveolar macrophage (AM)-driven lung inflammation plays an important role in PM-induced health effects. To further explore the potential mechanisms in an unbiased fashion, we performed RNAseq in AMs exposed to PM. In addition to NF-κB target genes (e.g., il6), we found immune response gene 1 (Irg1) as one of the top 10 genes induced by PM. Irg1 encodes aconitate decarboxylase 1 (Acod1), a mitochondrial enzyme that catalyzes the synthesis of itaconate. We found that PM-induced Irg1 expression occurred late, after the expression of il6 and other cytokines. As Irg1 protein was expressed, il6 expression declined. Treatment of AMs with itaconate decreased PM-induced il6, while deletion of Irg1 had an opposite effect and further increased PM-induced il6 expression. PM induced a unique metabolic reprogramming in AMs characterized by increased glycolysis and mitochondrial respiration, which is distinct from the effect of LPS (which reduces respiration). PM also induced mitochondrial ROS (mROS) from complex I (CI) via reverse electron transport (RET). Importantly, we found that both increased respiration and RET-driven mROS are required for PM-induced il6 expression. Itaconate inhibited the PM-induced increase in mitochondrial respiration, RET and resultant mROS via inhibition of succinate dehydrogenase (SDH) (CII) in AMs. Treatment with PM or itaconate reduced the inflammatory response (il6 and antiviral response genes) to bacteria, or influenza virus, suggesting that PM, via Irg1/itaconate/SDH inhibition may impair inflammatory response to pathogens. Based on these preliminary data, we hypothesize that PM first increases mitochondrial respiration, RET and mROS, which are required for the inflammatory response, followed by the late expression of Irg1/itaconate, which by inhibiting SDH, reduces mitochondrial respiration, RET, mROS, and suppresses inflammatory response leading to impaired response to pathogens. We will test our hypothesis in three specific aims. In aim 1, we will determine how increased mitochondrial respiration and Irg1/itaconate regulate PM-induced metabolic changes and transcriptional responses in AMs. In Aim 2, we will determine whether Irg1/itaconate suppresses the PM-induced transcriptional response by inhibiting reverse electron transport and mROS. In Aim 3, we will determine whether PM-induced Irg1/itaconate impairs the inflammatory response to subsequent infection. In this first study that explores the effects of PM on metabolism in AMs, concurrent analysis of the changes in metabolism with the transcriptional data will provide us with important knowledge about how metabolism derives the biologic effects induced by PM. Our investigation of how PM-induced Irg1/itaconate suppresses inflammatory response to pathogens has the potential to offer new therapeutic targets to prevent pneumonia induced by PM exposure.