# The Trojan Horse Hypothesis: Neutrophil Elastase Reprograms Macrophage Function

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $579,801

## Abstract

PROJECT SUMMARY
In Cystic Fibrosis (CF), airway innate immunity is breached. Macrophage phagocytosis and efferocytosis
fail, and macrophages augment airway inflammation by production of excess cytokines and release of
High Mobility Group Box 1 (HMGB1), a damage associated molecular pattern. Although loss of CFTR
impacts macrophage function, the CF airway milieu, which is typified by micromolar concentrations of
neutrophil elastase (NE), is an overwhelming stimulus, activating a robust pro-inflammatory response
in macrophages from both CF and healthy subjects. We propose that NE, a biomarker for lung disease
progression in CF subverts macrophage function from protective to pro- inflammatory, yet the
mechanisms by which NE reprograms the macrophage are not completely understood.
In this application, we present an unprecedented hypothetical mechanism to explain how NE alters
macrophage function. Extracellular NE is rapidly endocytosed by the macrophage. But instead of being
degraded, proteolytically active NE is localized to both cytoplasmic domains and the nucleus, resulting
in increased cytokine expression and release of macrophage extracellular traps (METs). Thus, NE
functions like a Trojan Horse to subvert macrophage function. We will test this hypothesis in primary
human blood monocyte derived macrophages from healthy volunteers and subjects with CF.
The Specific Aims follow:
Aim 1. To determine whether NE degrades HDACs, resulting in acetylation of downstream targets, leading to
transcriptional upregulation of TNFα and release of HMGB1.
Aim 2. To evaluate whether NE protease activity and/or NE-generated reactive oxygen species increase
release of mitochondrial and nuclear METs.
RELEVANCE: Results from this project will define a novel mechanism utilized by NE to promote
sustained airway inflammation, the major cause of morbidity and mortality in CF, and identify targets for
new therapies to interrupt the relentless progression of lung disease.

## Key facts

- **NIH application ID:** 9972145
- **Project number:** 1R01HL146811-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Judith A Voynow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $579,801
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972145

## Citation

> US National Institutes of Health, RePORTER application 9972145, The Trojan Horse Hypothesis: Neutrophil Elastase Reprograms Macrophage Function (1R01HL146811-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972145. Licensed CC0.

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