# Innate immune regulation of airway inflammation

> **NIH NIH U01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $423,750

## Abstract

Summary
The lung is a barrier surface of the mammalian body that is continuously exposed to microbes, allergens and
other irritants, and dysregulated immune responses to these stimuli underlies the pathogenesis of multiple
airway diseases, including asthma, COPD, IPF, and respiratory viral infections. Basic and translational
evidence suggests that populations of innate lymphoid cells (ILCs) are critical orchestrators of inflammation at
mucosal barrier sites. While recent research has defined the priming and downstream effector pathways of
ILCs in the lung, the cell-intrinsic mechanisms that limit ILCs or influence immune-regulatory responses remain
poorly understood. Based upon on our new preliminary data, this renewal will directly test the role of
two previously unknown ILC-intrinsic pathways in limiting inflammation in the lung.
Group 2 ILCs (ILC2) are a recently described populations of innate immune cells that are enriched in the lung
parenchyma that respond to epithelial-derived cytokines IL-25, IL-33 and TSLP, constitutively express the
transcription factor GATA3, and can mediate inflammatory processes in the lung through production of effector
cytokines IL-4, IL-5, IL-9 and IL-13 or promoting of a Th2 cell response. Despite their recent discovery and the
upstream pathways that promote ILC2 responses, it remains unclear what negatively regulates or turns off
ILC2 responses in the lung. In new preliminary data, we identify for the first time that ILC2 are enriched in
receptors for the Beta-2 adrenergic receptor (β2AR) pathway, a common drug target in asthma. Our new gain-
of-function and loss-of-function studies identify that the β2AR is essential to limit pathogen- and allergen-
induced ILC2 responses and inflammation at mucosal sites. Studies outlined in Aim 1 will directly test whether
the β2AR pathway is acting directly on ILC2 in a cell-intrinsic manner and mechanistically how the β2AR
pathway may regulate ILC2 responses. In contrast to type 2 cytokine-dominated inflammation in the lung,
recent translational studies suggest that a mixed Th2 and Th17 cell response in airway inflammation results in
more severe disease and often patients are refractory to most conventional therapies. Previously we defined
that group 3 ILCs (ILC3) directly limit dysregulated Th17 cell responses in the intestine of mice and humans
through MHCII-dependent interactions. In new studies, we now demonstrate that while the lung parenchyma is
dominantly populated with ILC2, RORγt+ group 3 ILCs (ILC3) are the dominant ILC group in the lung-draining
lymph node of healthy humans and mice. Further, in a model of chronic house dust mite (HDM)-induced lung
inflammation, mice with a genetic deletion of ILC3-intrinsic MHCII exhibited increased Th2 and Th17 cell
responses, granulocyte recruitment and airway inflammation. Collectively, these data provoke the central
hypothesis of Aim 2 that ILC3-intrinsic MHCII critically limits pathologic CD4+ T cells in the context of air...

## Key facts

- **NIH application ID:** 9961463
- **Project number:** 5U01AI095608-11
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** David Artis
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2011-07-25 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961463

## Citation

> US National Institutes of Health, RePORTER application 9961463, Innate immune regulation of airway inflammation (5U01AI095608-11). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9961463. Licensed CC0.

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