# Estrogen receptor signaling, inflammation and ozone toxicity

> **NIH NIH K99** · RUTGERS, THE STATE UNIV OF N.J. · 2021 · $117,880

## Abstract

Project Summary Abstract
Macrophages contribute to ozone toxicity by regulating both the initiation and resolution of lung inflammation;
these processes are mediated by distinct macrophage subpopulations broadly classified as
proinflammatory/cytotoxic (M1) and anti-inflammatory/wound repair (M2) macrophages. M1 and M2
macrophage activation is controlled, in part, by intracellular metabolism; thus, while high glycolytic capacity is
associated with M1 activity, increases in fatty acid oxidation and mitochondrial oxidative phosphorylation are
required for M2 macrophage activation. New data suggest that ozone toxicity is due to impaired M2 activation
and a failure to resolve inflammation, however, mechanisms are not known. A preliminary RNA-seq analysis of
lung macrophages collected after ozone exposure revealed significant enrichment of the estrogen receptor
signaling pathway among differentially expressed genes. This was associated with down-regulation of PPARγ
expression, a transcription factor known to promote M2 phenotype and resolution of inflammation by shifting
intracellular metabolism to fatty acid oxidation. Estrogen has been shown to regulate PPARγ expression by
activating estrogen receptor alpha (ESR1) located at the cell membrane, and to promote macrophage anti-
inflammatory activity by shifting metabolism to fatty acid oxidation; we speculate that this pathway is important
in macrophage responses to ozone. We hypothesize that ozone interferes with extra-nuclear ESR1
signaling in macrophages and downstream activation of PPARγ; this leads to impaired fatty acid
oxidation and M2 macrophage activation resulting in aberrant resolution of inflammation and
increased tissue injury. Three aims are proposed to test this hypothesis. In the first two aims (K99 period of
this award), we will analyze the effects of ozone on macrophage bioenergetics and the role for ESR1 signaling
in macrophage immunometabolism and phenotypic activation. Aim 3 (R00 award period) will focus on 1)
elucidation of mechanisms by which ozone interferes with extra-nuclear ESR1 signaling, 2) the role of extra-
nuclear ESR1 in macrophage bioenergetics and phenotype in response to ozone and how this influences lung
injury, and 3) developing strategies to mitigate ozone-induced lung injury by rescuing extra-nuclear ESR1
signaling. Results of these studies will provide novel data on mechanisms underlying macrophage responses
to inhaled ozone and represent a significant departure from the co-primary mentor’s areas of emphasis. The
career development plan will be performed at Rutgers University, a first-class institution with a strong training
environment and will consist of technical training and professional development activities. These will provide
the candidate with conceptual knowledge and training required to achieve his long-term goal of becoming an
established investigator at an academic research institution directing an independent research program
focused on elucidating ...

## Key facts

- **NIH application ID:** 10301740
- **Project number:** 1K99ES032473-01A1
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Ley C Smith
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $117,880
- **Award type:** 1
- **Project period:** 2021-08-06 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301740

## Citation

> US National Institutes of Health, RePORTER application 10301740, Estrogen receptor signaling, inflammation and ozone toxicity (1K99ES032473-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10301740. Licensed CC0.

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