# Neuroimmune interactions regulate development of allergic inflammation

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $582,345

## Abstract

PROJECT SUMMARY
Asthma is a highly prevalent inflammatory disorder of the airways that can lead to severe bronchoconstriction
and respiratory failure. Aberrant type 2 immune responses to allergens have long been appreciated as the
major driver of asthma. However, about 10% of patients have severe, persistent difficult to control asthma,
marked by the production of interleukin (IL)-17. This leads to neutrophilic airway inflammation, either alone or
in conjunction with type 2 inflammation, which responds poorly to current therapies, including corticosteroids.
These observations highlight the importance of identifying molecular targets capable of regulating both type 2
and type 17 responses in allergic lung inflammation. Innate lymphoid cells (ILCs), a recently described cell type,
have been shown to play a critical role in the initiation and amplification of mucosal tissue inflammation. ILC2s
rapidly produce pro-inflammatory cytokines like IL-5 and IL-13, which mediate eosinophil recruitment and
goblet cell hyperplasia, in response to epithelial alarmins like IL-25 and IL-33. ILC3s, on the other hand,
produce IL-17, and promote and propagate development of neutrophilic asthma. However, the molecular
mechanisms that promote pro-inflammatory phenotypes in ILC2s and ILC3s remain poorly understood,
particularly in the context of allergic airway inflammation,
We recently undertook massively parallel droplet-based single-cell RNA-sequencing to develop a
transcriptional atlas of lung resident ILCs under homeostatic and inflammatory conditions and identify novel
regulators of ILC function. We found that receptors for two different neuropeptides, neuromedin U (NMU) and
calcitonin gene related peptide (CGRP), were expressed on lung ILCs. Our data shows that NMU directly
activates ILCs in the presence of the alarmin IL-25 to acquire a pro-inflammatory phenotype. In contrast, the
neuropeptide CGRP inhibits ILC2 production of pro-inflammatory cytokines after stimulation with the alarmin
IL-33. These data lead us to hypothesize that following allergen challenge, neuronal signals via neuropeptide
receptors can potently modulate the ILC-mediated allergic inflammation. We propose three different aims to
address this hypothesis:
1) Identify and validate novel regulators of ILC function via single-cell transcriptional analysis of in
vivo-derived ILC2s and ILC3s; 2) Determine the mechanism(s) by which NMU/NMUR1 signaling
converts homeostatic ILCs into pro-inflammatory ILCs; 3) Study the mechanism by which the
neuropeptide CGRP regulates ILC2 function and development of allergic lung inflammation.
Together, these three aims will create a highly integrated transcriptional map of innate lymphoid cells (ILC2s
and ILC3s) during allergen exposure, and elucidate how the nervous system may regulate development of
allergic airway inflammation by activating neuropeptide receptors on ILCs.
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## Key facts

- **NIH application ID:** 9963113
- **Project number:** 5R01AI139536-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** VIJAY K. KUCHROO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $582,345
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963113

## Citation

> US National Institutes of Health, RePORTER application 9963113, Neuroimmune interactions regulate development of allergic inflammation (5R01AI139536-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963113. Licensed CC0.

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