Non-Classical Cytokine Secretion in Chronic Airway Disease

Abstract
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 epithelial-
derived 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.

Grant Number: 3R01HL152245-05S1
NIH Institute/Center: NIH
Principal Investigator: Jennifer Alexander-Brett