# PGI2 inhibition of pulmonary innate allergic immune responses

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Allergic airway inflammation is a hallmark of asthma, one of the most common chronic diseases in the United
States. The group 2 innate lymphoid cell (ILC2) is a recently described cell type that is a far more potent producer
of IL-5 and IL-13 on a per cell basis than CD4+ Th2 cells, and there is increasing evidence that ILC2 are critical
to the genesis and amplification of allergic inflammatory responses. In the last funding cycle of this VA Merit
Award, we reported that prostaglandin (PG) I2 negatively regulates ILC2 function, both in vitro and in vivo, while
inhibiting innate immunity-mediated airway eosinophilia, mucus metaplasia, and airways responsiveness,
cardinal features of the asthma phenotype. Our novel in vivo preliminary data strongly suggests that PGI2
signaling inhibits Alt Ex-induced airway release of IL-33, an alarmin cytokine that binds to the ST2 receptor on
ILC2 and other cells. Multiple genome wide association studies (GWAS) have identified IL-33 and ST2 as
asthma susceptibility loci. The experiments in this application have important clinical relevance as the NIH-
funded Severe Asthma Research Program (SARP) reported that gene expression for the PGI2 receptor (termed
PTGIR) in epithelial brushings was among the genes to best differentiate patients with severe asthma from those
with mild disease and healthy controls. In SARP, patients with severe asthma had significantly lower, but not
absent) gene expression of the PGI2 receptor. The long-term objectives of this application are to determine the
mechanisms by which decreased PGI2 receptor expression in the epithelium is associated with severe asthma
(Aim 1) and define the molecular mechanisms by which endogenous PGI2 signaling and exogenous PGI2 inhibit
ILC2 proliferation and function (Aim 2). Investigating the role of endogenous PGI2 is critical to understanding the
effect of cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications
in the world, on the innate allergic immune response as these agents inhibit PGI2 production. Investigating the
role of exogenous PGI2 is important to understand the potential effects of inhaled PGI2 or its analogs on the
innate allergic immune response as such agents are FDA approved and currently used therapeutically for
pulmonary hypertension, and therefore the use of which could be used to treat allergic respiratory diseases such
as asthma. These studies are paradigm shifting because there are currently no known FDA approved negative
regulators of aeroallergen-induced IL-33 release and our preliminary data strongly supports that PGI2 may be
the first described. Investigating the role of endogenous PGI2 is critical to understanding the effect of
cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications in the
world, on the innate allergic immune response as these agents inhibit PGI2 production. The proposed
experiments will advance the field in that they will ...

## Key facts

- **NIH application ID:** 10046277
- **Project number:** 5I01BX004299-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Ray Stokes Peebles
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046277

## Citation

> US National Institutes of Health, RePORTER application 10046277, PGI2 inhibition of pulmonary innate allergic immune responses (5I01BX004299-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10046277. Licensed CC0.

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