# Steroid resistance of airway ILC2s

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2022 · $456,531

## Abstract

Abstract:
The glucocorticoid-type steroids are the mainstay of asthma therapy. A subgroup of asthmatic patients
develops steroid resistance, which becomes a major therapeutic challenge and imposes a high cost to the
society. An understanding the mechanism of steroid resistance is important. Asthma is driven by the type 2
immune response. Type 2 innate lymphoid cells (ILC2s) are an important source of type 2 cytokines. Two
epithelial cytokines—IL33 and TSLP promote the development and function of ILC2s. We have recently
reported that airway ILC2s, as compared to blood ILC2s, from a subgroup of asthmatic patients are steroid
resistant in a TSLP (thymic stromal lymphopoietin)-dependent manner. Blood ILC2s become steroid resistant
when exposed to TSLP but not IL33. We have uncovered a mechanism for this dichotomous effect. Steroids
upregulate (protagonize) the receptors for TSLP but not IL33. By upregulating the receptors steroids lower
their activation threshold. Steroids still antagonize many inflammatory pathways in these cells but, surprisingly,
protagonize the pathways that directly interfere with the formation of the glucocorticoid receptor repressor
complex. Consequently, these pathways upregulate type 2 cytokines unabated in the presence of steroids,
which results in steroid resistance. Based upon these findings we hypothesize that activation of steroid
protagonized receptors induces steroid resistance through upregulation of select signaling pathways that
disrupt the formation of the glucocorticoid receptor (GR) repressor complex. We propose 3 specific aims to test
the foregoing hypothesis. Under specific aim 1 we will study the molecular mechanism of TSLP-induced
steroid resistance of ILC2s. We will examine how a novel signaling pathway involving MEK2-CBX7-PRC1,
identified in preliminary experiments, hinders the organization of the GR repressor complex. We will use
human blood and lung ILC2s to maintain human disease relevance. Specific aim 2 is devoted to mechanistic
and preclinical studies in mice. We will examine how repetitive exposure to allergens and rhinovirus
contributes to the development of steroid resistance. We will use genetically modified mice to validate the
importance of steroid resistant pathways. We will perform preclinical trials with pathway inhibitors in a
humanized mouse model of steroid resistant asthma. Under specific aim 3 we will establish the relevance of
TSLP and TSLPR signaling molecules for steroid resistance by studying bronchoalveolar lavage ILCs and T
cells from steroid resistant and steroid sensitive asthmatic patients. We will evaluate pathway inhibitors for
reversal of steroid resistance of airway lymphoid cells. We have all the necessary expertise, resources and
collaborators to accomplish this project. The proposal is important because it addresses an unresolved clinical
problem that affects not only asthma but also many chronic inflammatory, autoimmune and neoplastic
diseases where steroid resistance i...

## Key facts

- **NIH application ID:** 10400040
- **Project number:** 5R01AI137970-05
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Rafeul Alam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $456,531
- **Award type:** 5
- **Project period:** 2018-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400040

## Citation

> US National Institutes of Health, RePORTER application 10400040, Steroid resistance of airway ILC2s (5R01AI137970-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10400040. Licensed CC0.

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