# Non-Classical Cytokine Secretion in Chronic Airway Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $64,906

## Abstract

Abstract for the Parent Grant
Chronic lower respiratory tract disease is a major cause of morbidity and mortality in the U.S. and worldwide.
Currently there are no effective disease-modifying therapies and it remains unclear how to define and
optimally treat disease endotypes within the spectrum of asthma and COPD (chronic obstructive pulmonary
disease; chronic bronchitis and emphysema). This mechanistic research aims to define new pathways
amenable to therapeutic intervention based on the role of diseased airway epithelial cells as an upstream
driver of chronic airway disease. As a foundation for this proposal, multiple human clinical and translational
studies as well as allergen- smoke- and virus-induced animal models have solidified the relevance of the
pathogenic epithelialderived cytokine IL-33 in COPD and asthma. However, a major knowledge gap that
remains is understanding the mechanism by which nuclear-sequestered IL-33 can be activated and secreted
from diseased airway cells to drive inflammation. Here we present preliminary data that demonstrates
human COPD airway epithelial cells express increased levels of a truncated, spliced IL-33 isoform, which is
capable of escaping nuclear sequestration to be abundantly secreted. Our analysis further revealed novel
features of this secreted IL-33 isoform including post-translational modification, interaction with exosome-
associated chaperones, and utilization of exosome trafficking pathways for secretion. Accordingly, this study
aims to elucidate the impact of these newly-discovered features of IL-33 biology on the pathogenesis of
chronic airway disease. Aim 1 will define how IL-33 interaction with exosomal chaperones enhances
cytokine secretion and receptor activation to drive airway disease, using human cellular and mouse airway
disease models coupled with validation in human airway disease specimens. Aim 2 will investigate the role
of post-translational modification in augmenting IL-33 secretion and receptor activation to propagate
disease, through an analogous approach using human cellular and mouse models with validation in human
specimens. Together, these aims will address key steps in the pathologic sequence that initiates and
sustains chronic airway disease, illuminating novel ways to target exosome-mediated cytokine secretion at
the mucosal interface
Abstract for the Supplement
Chronic lower respiratory tract disease is a major cause of morbidity and mortality in the U.S. and worldwide.
Currently there are no effective disease-modifying therapies and it remains unclear how to define and optimally
treat disease endotypes within the spectrum of asthma and COPD (chronic obstructive pulmonary disease;
chronic bronchitis and emphysema). This mechanistic research aims to define new pathways amenable to
therapeutic intervention based on the role of diseased airway epithelial cells as an upstream driver of
chronic airway disease. As a foundation for this proposal, multiple human clinical and tra...

## Key facts

- **NIH application ID:** 10993467
- **Project number:** 3R01HL152245-04S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jennifer Alexander-Brett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $64,906
- **Award type:** 3
- **Project period:** 2024-03-05 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993467

## Citation

> US National Institutes of Health, RePORTER application 10993467, Non-Classical Cytokine Secretion in Chronic Airway Disease (3R01HL152245-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10993467. Licensed CC0.

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