# Neutrophil responses Drive Severe Asthma

> **NIH NIH U19** · NORTHWESTERN UNIVERSITY · 2024 · $588,417

## Abstract

PROJECT 2 ABSTRACT: Asthma is the most common chronic lung disease worldwide. Importantly, over half
of the $3.1B spent in the U.S. each year on asthma health care costs derive from less than 10% of patients,
those who experience severe disease. Roughly, half of patients with severe asthma exhibit eosinophilic airway
inflammation driven by type 2 (T2) cytokines (IL-4, IL-5, and IL-13). T2 inhibitor drugs are highly effective in
blocking exacerbations among T2 patients with eosinophil-predominant disease. However, the remaining 50%
with non-T2 disease are without treatment options and have poorly understood pathobiology. This represents
the greatest unmet need in asthma. We have found non-T2 asthma includes those with interferon-γ-driven T1
and IL-17-driven T17 inflammation. A central feature of these T1 and T17 endotypes is persistent airway
neutrophilia, accompanied by airway obstruction and remodeling. Moreover, we find that a subgroup of T2
patients also exhibit airway neutrophilia. At National Jewish, we have integrated translational research
infrastructure into our high-volume clinical asthma program, allowing for the collection of airway epithelium and
biopsies, bronchoalveolar lavage, sputum cells, and blood from patients with severe asthma. These biosamples
collected from well-phenotyped patients provide the opportunity to evaluate mechanisms controlling the
infiltration, activation, and function of airway neutrophils in severe asthma. Here, we challenge the notion that
neutrophils are a static, homogeneous population, playing a simple pathogen response role in the airway. Rather
our data suggest that neutrophil subsets could be differentially recruited to, and programmed by, the airways of
T2, T1, and T17 asthmatics, through their expression of different combinations of neutrophil chemoattractant
genes (CXCL1/3/8, C3), survival/maturation genes (CSF3), and activation genes (IFNG, IL17). At the same time,
we find that neutrophils are potent producers of cytokines (e.g. IL-1α/β, IL-6) that induce airway remodeling and
epithelial dysfunction. Therefore, we hypothesize that airway recruitment and mucosal programming of
neutrophils in severe asthma occur in a T2, T1, and T17 endotype-specific manner, resulting in unique neutrophil
inflammatory, immunomodulatory, and proteolytic activities that drive airway epithelial remodeling. To test this
hypothesis, we will perform single-cell and spatial transcriptomic sequencing of circulating and airway neutrophils
from well-phenotyped severe asthma patients. These in vivo molecular data will be paired with data from ex vivo
functional assays and from the modeling of neutrophil-epithelial circuits using airway organoid cultures. In Aim 1
we will determine whether T2, T1, and T17 airway mucosal niches direct differential recruitment of circulating
neutrophil heterogeneity through CXCL1/3/5/8, C5, and LTB4. In Aim 2 we will determine the role of T2, T1, and
T17 airway mucosal programming factors (CSF3, I...

## Key facts

- **NIH application ID:** 10824515
- **Project number:** 1U19AI181102-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Max A Seibold
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $588,417
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824515

## Citation

> US National Institutes of Health, RePORTER application 10824515, Neutrophil responses Drive Severe Asthma (1U19AI181102-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10824515. Licensed CC0.

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