# Harnessing Inflammatory Macrophages to Thwart Lung Disease Caused by Chronic Ozone Exposure

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $549,121

## Abstract

ABSTRACT
Uncontrolled inflammation is central to the pathophysiology of asthma and COPD which can develop following
chronic exposure to ozone. Evidence suggests that these pathologies are due to an inability to adequately
resolve the acute inflammatory response to lung injury. This suggests that promoting the resolution of
inflammation will be more beneficial than suppressing persistent unrestrained inflammation. Our studies are
focused on macrophages which play a key role in both initiating and resolving inflammatory responses to
tissue injury. This activity is mediated by distinct subsets broadly classified as proinflammatory M1 and
proresolution M2 macrophages. Effective resolution of inflammation depends on metabolic reprogramming of
macrophages from an M1 phenotype to an M2 phenotype, which involves a switch from glycolysis to oxidative
phosphorylation as a source of energy. We discovered that this reprogramming is suppressed following chronic
ozone exposure. The goal of our studies is to analyze mechanisms underlying suppression of macrophage
reprogramming. In recent studies we identified farnesoid-X receptor (FXR), a nuclear receptor important in bile
acid metabolism, with anti-inflammatory activity, as important in promoting M1 to M2 macrophage
reprogramming in the lung. Following ozone exposure, macrophage FXR activity is downregulated. This is
associated with increased activity of proinflammatory M1 macrophages and reduced activity of proresolving M2
macrophages. We also found that microRNAs that regulate the proinflammatory transcription factor NFκB are
dysregulated in macrophages after ozone exposure. As a consequence, there is protracted activation of NFκB
signaling resulting in increased production of TNFα, IL-1β, and cytotoxic reactive nitrogen species. We
hypothesize that these mediators suppress FXR activity which prevents activation of the nuclear receptor
NR4A1, a key inducer of macrophage M1 to M2 metabolic reprogramming. To test this hypothesis, we will (1)
Determine if persistent inflammation following chronic ozone exposure and the development of lung disease is
due to defective development of proresolution M2 macrophages, and assess whether this is caused by
protracted activation of NFκB in M1 macrophages; (2) Analyze the role of FXR and its target NR4A1, in the
development of proresolution M2 macrophages in the lung following chronic ozone exposure; and (3)
Determine if protracted activation of NFκB is due to ozone-induced alterations in microRNAs regulating NFκB.
Results of these studies will provide new mechanistic insights into chronic ozone toxicity and may lead to the
development of new approaches for thwarting the development of chronic lung disease.

## Key facts

- **NIH application ID:** 10751045
- **Project number:** 5R01ES033698-03
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Debra L Laskin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $549,121
- **Award type:** 5
- **Project period:** 2022-02-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10751045

## Citation

> US National Institutes of Health, RePORTER application 10751045, Harnessing Inflammatory Macrophages to Thwart Lung Disease Caused by Chronic Ozone Exposure (5R01ES033698-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10751045. Licensed CC0.

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