# Activated Macrophages and Ozone Toxicity

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2022 · $566,220

## Abstract

ABSTRACT
Ozone is a ubiquitous air pollutant and the main component of photochemical smog. It remains a federally
regulated air pollutant of ongoing public health concern. Inhaled ozone irritates and damages the lung in both
healthy and susceptible individuals, including children and the elderly. Ozone causes inflammation and
constriction of the airways, reducing pulmonary function. Ozone also exacerbates asthma and chronic lung
disease. Thus, elucidating mechanisms of toxicity is highly relevant in terms of identifying new strategies to
reduce lung injury from ozone and potentially other air pollutants. Our studies are focused on macrophages,
which we have demonstrated play a key role in both initiating and resolving inflammatory responses to ozone-
induced tissue injury. These activities are mediated by distinct subsets broadly classified as proinflammatory
M1 and proresolution M2 macrophages. Effective resolution of inflammation following tissue injury 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 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 regulating lipid metabolism, with anti-inflammatory activity, as central to
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 inflammatory
mediators. We hypothesize that these mediators suppress FXR activity which prevents activation of the PPARγ
coactivator (PGC-1β), an inducer of macrophage M1 to M2 metabolic reprogramming. To test this hypothesis,
we will perform parallel studies in mice and humans and (1) Determine if persistent inflammation following
ozone exposure and lung injury is due to impaired development of proresolution M2 macrophages, and assess
whether this is caused by protracted activation of NFκB; (2) Analyze the role of FXR and its target, PGC-1β in
the development of proresolution M2 macrophages in the lung following ozone exposure; and (3) Assess
whether protracted activation of NFκB is a consequence of ozone-induced alterations in microRNAs regulating
NFκB. Results of these studies will provide new mechanistic insights into ozone toxicity. This will have
significant translational implications for the development of new strategies for preventing and treating the
toxicity of ozone, and p...

## Key facts

- **NIH application ID:** 10521455
- **Project number:** 2R01ES004738-26A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Debra L Laskin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $566,220
- **Award type:** 2
- **Project period:** 1989-06-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521455

## Citation

> US National Institutes of Health, RePORTER application 10521455, Activated Macrophages and Ozone Toxicity (2R01ES004738-26A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10521455. Licensed CC0.

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