# Androgens inhibit IL-33 production and airway inflammation

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $659,803

## Abstract

Severe asthma patients have a high morbidity and utilize >50% of asthma-related health care
each year. IL-33 signaling through its receptor, ST2 (IL1RL1), drives allergic airway
inflammation, airway hyperresponsiveness, and mucus production by increasing IL-4, IL-5, and
IL-13 production from Th2, group 2 innate lymphoid cells (ILC2), and other cells types. While
anti-IL-33 is a promising asthma therapeutic, additional understanding of pathways the regulate
this pathway could lead to novel therapeutic options in this patient population. In the previous
funding period, we determined how ovarian hormones increased IL-17A and type 2-mediated
airway inflammation in severe asthma, which is most common in women. Through the course of
these studies we also found that that androgen receptor (AR) signaling attenuated Th17 cell
differentiation, ILC2 proliferation, and allergic airway inflammation. Gonadectomized male mice
(which lack androgens) also had increased Alt Ext-induced IL-33 compared to hormonally intact
male mice. Yet, the mechanisms by which AR signaling attenuates allergen-induced airway
inflammation were unclear. Androgens signaling through the AR are associated with increased
lung function and decreased asthma symptom scores in women and men with asthma. New
preliminary data for this application suggest that AR signaling decreases allergic airway
inflammation by decreasing the release of active IL-33, sustaining T regulatory cells (Tregs)
stability and suppressive function, and decreasing ST2 expression on Th2 and ILC2 cells to limit
IL-33-mediated allergic airway inflammation. We hypothesize that AR signaling post-
transcriptionally modifies IL-33 to limit release, restrains downstream IL-33 signaling by
inhibiting ST2 expression and signaling, and stabilizes Treg suppressive function. To test this
hypothesis, we will use primary, differentiated bronchial epithelial cell and immune cells from the
excised lungs and lymph nodes of women and men with asthma as well as mouse models of
asthma to: Aim 1) Determine the mechanisms by which AR signaling limits IL-33 release from
human bronchial epithelial cells, Aim 2) Delineate how AR signaling potentiates Treg stability
and suppressive function during allergic airway inflammation, and Aim 3) Determine if AR
signaling decreases ST2 expression and downstream signaling on Th2 cells to reduce allergic
airway inflammation. Delineating how AR signaling attenuates IL-33 release while maintaining
lung Treg function will be critical for personalizing therapies for women and men with severe
asthma and potentially other IL-33-mediated diseases.

## Key facts

- **NIH application ID:** 10791871
- **Project number:** 5R01HL122554-10
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Dawn C Newcomb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,803
- **Award type:** 5
- **Project period:** 2014-12-22 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791871

## Citation

> US National Institutes of Health, RePORTER application 10791871, Androgens inhibit IL-33 production and airway inflammation (5R01HL122554-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10791871. Licensed CC0.

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