# Role of alveolar macrophages in particulate matter-induced cardiopulmonary disease

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $433,527

## Abstract

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....

## Key facts

- **NIH application ID:** 10407017
- **Project number:** 5R01ES015024-15
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Gokhan M. Mutlu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $433,527
- **Award type:** 5
- **Project period:** 2006-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407017

## Citation

> US National Institutes of Health, RePORTER application 10407017, Role of alveolar macrophages in particulate matter-induced cardiopulmonary disease (5R01ES015024-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407017. Licensed CC0.

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