# Origin and Function of Intra-epithelial Mast Cells in Asthma

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $760,773

## Abstract

Project Summary
Airway hyperresponsiveness (AHR) is a fundamental feature of asthma and is the hallmark of the disease in
the majority of patients with asthma. Our lab has been working to understand the underlying
immunopathogenesis of AHR and recently discovered using three-dimensional quantitative imaging of the
airway wall that in asthma there is a shift in mast cells (MC)s from the submucosa to the airway epithelium that
is closely related to the severity of AHR as well as features of type-2 (T2) inflammation. This shift is critical as
we identified a IL-33 dependent feed-forward loop in which MCs regulate the expression of epithelial IL-33
(IL33), indicating that MCs serve not only as effector cells but also regulate T2 inflammation through IL-33.
This feed-forward loop is accentuated in airway epithelial cells (AEC)s from individuals with asthma indicating
that the unique microenvironment that is established by the epithelium in asthma is critical for the propagation
of AHR and T2 inflammation through this feed-forward interaction between MCs and the airway epithelium.
The major goals of this research are to identify the underlying basis for MC infiltration of the airway
epithelium, the molecular details of this interaction between MCs and primary AECs from individuals
with asthma and the in vivo relevance of the IL-33-MC-axis using selected murine models of asthma.
Given that mature MCs arise from circulating progenitors, we hypothesize that the number of MC progenitors
(MCP)s in the airways is increased in asthma, and these cells function in concert with the susceptible airway
epithelium to orchestrate T2 inflammation. We will directly address our hypothesis by using airway samples
and primary AECs from individuals with and without asthma and/or allergic sensitization, combined with AEC-
MC coculture models, and murine models of asthma in which we examine the function of the IL-33-MC-axis. In
specific aim 1, we investigate the differences in the number and proliferation potential of MCPs in the airways
and peripheral blood of subjects with asthma and AHR, relative to non-asthmatic control subjects with and
without allergic sensitization. We further examine the expansion of MCPs in the airways following allergen
challenge in individuals with asthma. In specific aim 2, we determine how the asthmatic airway epithelium
interacts with MCs to regulate T2 inflammation, using an ex vivo model of primary AECs from subjects with and
without asthma to examine this feed-forward mechanism. In specific aim 3, we use selective IL-33 receptor
deletion in MCs in an in vivo model to understand how IL-33 acts through MCs to regulate the development of
T2 inflammation and AHR. The completion of these studies using airway samples, phenotyped AECs, and
sophisticated murine models will move the field forward through a better understanding of the interplay
between AECs and intraepithelial MCs that serve to regulate AHR and the T2 immune response.

## Key facts

- **NIH application ID:** 10218653
- **Project number:** 1R01HL153979-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Teal S. Hallstrand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $760,773
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218653

## Citation

> US National Institutes of Health, RePORTER application 10218653, Origin and Function of Intra-epithelial Mast Cells in Asthma (1R01HL153979-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218653. Licensed CC0.

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