# Control of Pulmonary Inflammation by Leukotriene E4

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $700,679

## Abstract

Abstract/Summary
This application for continuing support focuses on the mechanisms by which the cysteinyl leukotrienes
(cysLTs), a class of potent lipid inflammatory mediators, facilitate type 2 (eosinophilic) immunopathology (T2I)
that underlies prevalent and burdensome respiratory diseases, including asthma and chronic rhinosinusitis with
nasal polyps (CRSwNP). The proposal tests the hypothesis that leukotriene E4 (LTE4) initiates respiratory T2I
through engagement of the type 3 cysLT receptor (CysLT3R) and nucleotide signaling to P2Y2 receptors on
brush cells (BrCs). A second hypothesis is that LTE4-induced BrC activation elicits activation of group 2
innate lymphoid cells (ILC2s) and type 2 cytokine generation through synergistic actions of IL-25 and
endogenously generated LTC4. A third hypothesis is that IL-25-driven eosinophil recruitment provides a pool
of LTC4-driven platelet-derived IL-33 to incrementally activate ILC2s and MCs, further amplifying T2I and its
consequences, including upstream BrC expansion. The proposal uses a combination of novel transgenic mice,
ex vivo approaches, and unique models to dissect a complex pathway by which cysLTs act in series
downstream of epithelial perturbation by leukotriene E4, the most stable cysLT, to activate MC, potently elicit
ILC2 activation, and induce severe immunopathology. The studies seek to explain the selective
hyperresponsiveness of asthmatic subjects to leukotriene E4, and to develop therapeutic strategies through the
selective targeting of receptors other than CysLT1R.

## Key facts

- **NIH application ID:** 10296403
- **Project number:** 2R01AI078908-12A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Joshua A Boyce
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $700,679
- **Award type:** 2
- **Project period:** 2021-08-13 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296403

## Citation

> US National Institutes of Health, RePORTER application 10296403, Control of Pulmonary Inflammation by Leukotriene E4 (2R01AI078908-12A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10296403. Licensed CC0.

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