# PGI2 regulation of CD4+ Th2 metabolism in allergic airway inflammation

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Asthma is one of the most common chronic diseases in the United States. There is mounting evidence
that medications that inhibit the cyclooxygenase (COX) pathway of arachidonic acid metabolism are linked to
new onset asthma, strongly suggesting that COX metabolic products inhibit the development of asthma.
These data are supported by numerous mechanistic animal studies published by the Principal Investigator (PI)
which revealed that COX inhibition increased lung expression of the CD4 T helper 2 (Th2) cytokines IL-5 and
IL-13 that are important in airway eosinophilia, mucus expression, and airway responsiveness (AR), all
hallmarks of allergic asthma. Several studies by the PI and other groups revealed that the COX product
prostaglandin (PG)I2 restrains the development of allergic inflammation by inhibiting proinflammatory cytokine
secretion by CD4 Th2 cells; however, the mechanisms by which PGI2 exerts these anti-inflammatory effects
are not completely defined. Our novel, unpublished preliminary data reveals that
PGI2
signaling inhibited
glycolysis, glycolytic capacity, and glycolytic reserve in CD4 Th2 cells, suggesting that PGI2 has a
critical role in CD4 T cell immunometabolism. We provide evidence in our preliminary data that PGI2
decreases CD4 Th2 expression of Glut1, the glucose transporter that is essential for the uptake of glucose and
amino acids into the cell and which is required for glycolysis. Additional preliminary data of targeted
metabolomics identified the glutamine metabolism pathway as being substantially regulated when CD4
Th2 cells were polarized in the presence or absence of the PGI2 analog cicaprost. However, the
mechanisms by which
PGI2
signaling inhibits glycolysis and the glutamine metabolic pathway are not known.
In this application, we will test the overall hypothesis that PGI2 restrains allergen-induced airway
inflammation by inhibiting glucose and glutamine metabolism in Th2 effector cells, thus defining the
immunometabolic mechanisms by which PGI2 restrains allergic inflammation in the lung.
 In this application, we will use complementary genetic and pharmacologic approaches, both in vivo and
in in vitro experiments using primary CD4 T lymphocytes. We will create novel model organisms to definitively
determine how regulates glycolysis and glutamine metabolism using conditional mice floxed for the PGI2
receptor IP, that were specifically created through funding of the last cycle of this Merit Award. This current
Merit proposal is clinically relevant in defining the immunometabolic mechanisms by which PGI2 inhibits CD4
differentiation and function in allergic airway inflammation, thus providing support for the use of PGI2 in the
treatment of allergic diseases such as asthma. The proposed experiments will be paradigm shifting by being
the first to define how a prostaglandin regulates immunometabolism and will advance the field and the health
of our nation's Veterans by discovering new therapeutic pathways for diseases t...

## Key facts

- **NIH application ID:** 10867329
- **Project number:** 5I01BX004299-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Ray Stokes Peebles
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867329

## Citation

> US National Institutes of Health, RePORTER application 10867329, PGI2 regulation of CD4+ Th2 metabolism in allergic airway inflammation (5I01BX004299-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867329. Licensed CC0.

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