# Project 1: Eicosanoid Regulation of Type 2 Immunity in AERD

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $803,454

## Abstract

Abstract
This Project focuses on the mechanisms by which structural cell-derived “level 1” innate type 2 cytokines
interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) drive the production of pathogenic eicosanoids
(particularly prostaglandin (PG)D2 and thromboxane (TX)A2)) by mast cells (MCs) in the respiratory mucosa,
and by which those eicosanoids in turn amplify inflammation secondary to the innate type 2 immune system
through effects on blood-born effector cells. Impaired PGE2 production and/or receptor function permits the
initiating events to drive a feed forward loop, resulting in persistent respiratory mucosal inflammation,
hyperplastic eosinophilic sinusitis, recurrent nasal polyposis, and severe asthma that characterize AERD. The
central hypothesis is that respiratory inflammation is controlled by a balance between the effects of inductive
(IL-33 and TSLP) and suppressive (PGE2) factors derived from persistently activated structural cells. AERD
results from imbalances in this system that lower the threshold for the activation of MCs and other effector
cells, resulting in overproduction of pathogenic eicosanoids (PGs, cysteinyl leukotrienes (cysLTs), and
recruitment and/or activation of eosinophils, basophils, type 2 innate lymphoid cells (ILC2s), other lymphoid
populations, and platelet-adherent granulocytes. Aim 1 is to identify the cellular source(s) of IL-33, TSLP, and
prostaglandin (PG)E2 in nasal polyps and to determine the extent to which the endogenous cytokines drive MC
eicosanoid generation in aspirin exacerbated respiratory disease (AERD). Aim 2 is to identify factors from
nasal polyp structural cells that prime local MCs and regulate their transcriptional profile. Aim 3 is to determine
the importance of MC and structural cell-derived eicosanoids in driving accumulation and activation of effector
cells of innate and adaptive immunity in the respiratory tissue. The data in this Project will be incorporated by
Core B with data from Project 2 to build a predictive network model for AERD pathogenesis that will inform all
three projects.

## Key facts

- **NIH application ID:** 9973140
- **Project number:** 5U19AI095219-10
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Joshua A Boyce
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $803,454
- **Award type:** 5
- **Project period:** — → 2021-07-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973140

## Citation

> US National Institutes of Health, RePORTER application 9973140, Project 1: Eicosanoid Regulation of Type 2 Immunity in AERD (5U19AI095219-10). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/9973140. Licensed CC0.

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