# Epigenetic regulation of chemokines in lung inflammation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $390,598

## Abstract

Neutrophilic inflammation is the dominant lung pathology in cystic fibrosis (CF) which is
associated with elevated Interleukin-17 production. Our long-term goal is to elucidate
the regulation of IL-17 production and dissect the downstream neutrophilic responses in
the lungs. IL-17 promotes the production of CXCR2 ligands including CXCL5, which has
chemotactic and activating functions on neutrophil especially during acute inflammatory
responses. Preliminary data indicate that IL-17 augments the expression of these
chemokines through histone modification. Although IL-17 can promote inflammation
through stabilizing mRNAs encoding CXCR2 ligands, the epigenetic regulation
described in this proposal is novel and could have significant clinical impact on treatment
and diagnosis of chronic inflammatory diseases. We hypothesize that IL-17 enhances
CXCR2 ligands production in the epithelium through increasing chromatin
accessibility by repressing HDAC5 and that IL-17 induced epithelial CXCL5 is
required for chronic neutrophilic inflammation in the lungs. In Aim1, we will
determine the roles of epithelial IL-17 receptors in regulating optimal Cxcl5 expression
and neutrophil recruitment in chronic inflammation. We will use conditional IL-17R KO
mice in established murine models mimicking neutrophilic lung disease in humans. In
Aim2, we will determine if the IL-17 induced expression of CXCR2 ligands requires
histone deacetylase HDAC5, identified from the preliminary studies. In Aim3, we will
seek to inhibit IL-17 mediated lung inflammation in vivo using compounds that disrupt
chromatin remodeling and gene expression. The long-term goal of this research will be
to maximize the clinical benefit of targeting the IL-17 pathway in chronic inflammation by
defining the epigenetic mechanism of IL-17 driven expression of chemokines. This
application seeks to shift current research and clinical practice paradigms by
identification of a novel epigenetic regulatory mechanism by which IL-17 promotes
neutrophilc inflammation in CF epithelium. The findings generated from these aims may
have profound translational implications not only to CF but also to other neutrophilic
inflammatory conditions.

## Key facts

- **NIH application ID:** 10237370
- **Project number:** 5R01HL137709-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kong Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,598
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237370

## Citation

> US National Institutes of Health, RePORTER application 10237370, Epigenetic regulation of chemokines in lung inflammation (5R01HL137709-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10237370. Licensed CC0.

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