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Role of alveolar macrophages in particulate matter-induced cardiopulmonary disease

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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-?B 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.

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