# Nuclear receptor, PPARg in macrophage polarization, hyperinflammatory gene expression and lung injury

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $642,244

## Abstract

PROJECT SUMMARY
Hyperinflammatory gene expression upon tissue injury is a major health risk and the cause of significant
morbidity and mortality, particularly if it occurs in the lung. The polarization and injury-responsiveness of
macrophages (MF) is tightly regulated to ensure proper control of homeostatic, inflammatory, anti-inflammatory
and regenerative processes. The transcriptional and epigenomic determinants of (hyper)responsiveness are
poorly understood. We have recently determined that the nuclear hormone receptor, Peroxisome Proliferator
Activated Receptor gamma (PPAR) is part of a transcription factor cascade in Interleukin (IL)4 polarized MFs,
downstream of the Signal Transducer and Activator of Transcription (STAT)6 induced Early Growth Regulator
(EGR)2. Remarkably, PPAR proved to have ligand-dependent, but also apparently ligand-independent,
epigenomic activities controlling alternative polarization. In addition, we can show that IL-4 polarized MFs
establish a unique epigenome and inflammatory gene expression program upon Toll-Like Receptor (TLR)-ligand
exposure. A newly identified part of this interaction, we termed extended synergy, is dependent on the expansion
of Nuclear Factor (NF)κB-p65 cistrome and increased enhancer activity. The previously alternatively polarized
MFs produce immune-modulatory factors, including Chemokine (C-C) Ligand (CCL) 2, IL6 at an extremely high
level in vitro and in vivo in a murine Th2-type airway inflammation and lung injury model upon lipopolysaccharide
(LPS) exposure leading to exacerbation of the response. The extended synergy and the LPS response of several
genes, including Ccl2 and Il6, depend on the presence of PPAR and some can be modulated by its synthetic
and selective ligand, Rosiglitazone. We hypothesize that PPAR acts as signal-dependent epigenomic
bookmark, selecting and safeguarding enhancers during MF-extended synergistic inflammatory gene expression
by modulating the amplitude of the response. The receptor acts via two distinct mechanisms (1) actively selecting
and inducing enhancers genome-wide and (2) also as epigenomic bookmarker and architectural factor altering
gene expression only upon non-cognate inflammatory signals. We are examining these hypotheses by
systematically mapping the transcriptional and epigenomic changes requiring PPAR, the receptor’s role in the
dynamically changing 3D chromatin architecture and in mouse models of lung injury, Th2 inflammation and the
combination of the two leading to a hyperinflammatory response leading to exacerbation of these disease
processes. Using cutting-edge epigenomics and transcriptomics technologies, with innovative genetic and
chimeric mouse models analyzed by high dimensional flow cytometry and single cell technologies will provide
mechanistic insights into this novel mode of action of the nuclear receptor PPAR and may lead to the
identification of novel pathways to alleviate lung injury and disease progression.

## Key facts

- **NIH application ID:** 10883068
- **Project number:** 2R01HL170426-05A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Laszlo Nagy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $642,244
- **Award type:** 2
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883068

## Citation

> US National Institutes of Health, RePORTER application 10883068, Nuclear receptor, PPARg in macrophage polarization, hyperinflammatory gene expression and lung injury (2R01HL170426-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883068. Licensed CC0.

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