Role of alveolar macrophages in particulate matter-induced cardiopulmonary disease

肺泡巨噬细胞在颗粒物诱发的心肺疾病中的作用

• 批准号: 10163187
• 负责人: Gokhan M. Mutlu
• 金额: $ 43.35万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163187
• 关键词: Aconitic Acid; Acute; Affect; Air Pollution; Alveolar Macrophages; Antiviral Response; Attenuated; Bacteria; Biological; Carboxy-Lyases; Cardiopulmonary; Cells; Cessation of life; Complex; Cytochrome c Reductase; Data; Dose; Electron Transport; Environmental Health; Enzymes; Event; Exposure to; Genes; Genetic Transcription; Glycolysis; Goals; Grant; Health; Heart Diseases; ITGAX gene; Immune Response Genes; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Interleukin-6; Investigation; Ionophores; Knowledge; Lung; Lung Inflammation; Lung diseases; Measures; Mediating; Membrane Potentials; Metabolic; Metabolism; Metformin; Mitochondria; Mus; Particulate Matter; Play; Pneumonia; Proteins; Pulmonary Heart Disease; Reporting; Resistance; Respiration; Role; Succinate Dehydrogenase; Succinates; Testing; Tissues; air filter; alternative oxidase; base; cytokine; experimental study; global environment; in vivo; influenzavirus; inhibitor/antagonist; insight; macrophage; mitochondrial membrane; mitochondrial metabolism; mortality; new therapeutic target; pathogen; premature; prevent; response; transcriptome sequencing

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.

颗粒物 (PM) 空气污染是一个全球性环境健康问题，导致 370 万人过早死亡 每年死亡人数，占全球死亡人数的 6.7%。这些死亡主要是由于急性发作增加 心肺疾病，包括肺炎。虽然机制尚不完全清楚，但肺泡 巨噬细胞 (AM) 驱动的肺部炎症在 PM 引起的健康影响中发挥着重要作用。为了进一步 为了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 除了 NF-κB 靶基因（例如 il6）外，我们还发现免疫应答基因 1 (Irg1) 是排名前 10 的基因之一 由 PM 引起。 Irg1 编码乌头酸脱羧酶 1 (Acod1)，这是一种催化 衣康酸的合成。我们发现 PM 诱导的 Irg1 表达发生较晚，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。用衣康酸治疗 AM 减少 PM 诱导的 il6，而删除 Irg1 则产生相反的效果，进一步增加 PM 诱导的 il6 表达。 PM 在 AM 中诱导独特的代谢重编程，其特征是糖酵解增加和 线粒体呼吸，这与 LPS（减少呼吸）的作用不同。 PM也诱发 通过反向电子传递 (RET) 从复合物 I (CI) 产生线粒体 ROS (mROS)。重要的是，我们发现 PM 诱导的 il6 表达需要增加呼吸作用和 RET 驱动的 mROS。衣康酸抑制 PM 通过抑制琥珀酸诱导线粒体呼吸、RET 和由此产生的 mROS 增加 AM 中的脱氢酶 (SDH) (CII)。 PM 或衣康酸治疗可减轻炎症反应（il6 和 抗病毒反应基因）对细菌或流感病毒，表明 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 mROS， 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，并抑制炎症反应，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 来响应。在目标 3 中，我们将确定 PM 是否引起 Irg1/衣康酸会损害随后感染的炎症反应。在这第一项研究中，探讨了 PM对AM代谢的影响，同时分析代谢与转录的变化 数据将为我们提供关于新陈代谢如何产生 PM 引起的生物效应的重要知识。 我们对 PM 诱导的 Irg1/衣康酸如何抑制病原体炎症反应的研究表明： 可能提供新的治疗靶点来预防 PM 暴露引起的肺炎。