# Epigenetic Regulation of Prostaglandin E2 (PGE2) Synthesis Alters Macrophage Function to Promote Inflammation and Impair Diabetic Wound Healing

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $450,549

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and
are increasing at an alarming rate. Failure of wound healing in T2D patients represents the most common
cause of amputation in the US with a 5-year mortality rate of nearly 50%. Thus, a critical need exists for
understanding the wound healing defects in T2D in order to develop targeted therapies. We have utilized both
genetic (db/db) and dietary (diet-induced obese) murine models of T2D as well as human wound tissue and
blood samples collected from T2D patients to explore mechanisms of impaired wound healing. Our published
and preliminary data point to a pivotal role for macrophage (Mφ) function in orchestrating appropriate wound
healing and demonstrate that wound Mφs in diabetic mice and patients with T2D are characterized by a
persistent inflammatory state, impaired phagocytosis/killing and the over-production of the immunomodulatory
lipid, prostaglandin E2 (PGE2). Our data demonstrate epigenetic regulation of key genes important for the
production of PGE2, namely cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), and show
overexpression of PGE2 in Mφs results in increased production of inflammatory mediators such as interleukin
1β (IL1β) and impaired host defense against bacterial pathogens that often colonize the wound bed. Our
preliminary data are the first to identify that cPLA2/COX-2 and PGE2 are increased in diabetic wound Mφs and
that this pathway may be regulated by multiple epigenetic mechanisms, including DNA methylation and histone
methylation, in both diet-induced and genetic models of diabetes. These results support our hypothesis that
inhibition of the COX-2/PGE2 pathway in Mφs is critical for resolution of inflammation and proper host defense
that is required for effective wound repair. These results have led to our hypothesis that the COX-2/PGE2
pathway is epigenetically regulated and increased in diabetic wound Mφs and this results in increased
inflammation, impaired host defense and defective wound repair. Our data suggest that wound Mφ function
may be restored via Mφ-targeted treatment of FDA-approved COX inhibitor(s), TGFβ signaling receptors
and/or the first-ever developed EP2-specific antagonist. To test our hypotheses, we will: Aim 1: Determine the
regulation of cPLA2 to release AA and promote COX-2/PGE2 production in diabetic wound Mφs. Aim 2:
Determine whether TGFβ-induced miR-29b causes hypomethylation of the COX-2 gene to increase COX-2
and PGE2 production in diabetic wound Mφ and evaluate the therapeutic efficacy of Mφ targeted COX-2
inhibition and TGFβ receptor antagonists. Aim 3: Determine the Mφ-specific PGE2-mediated mechanism(s)
that modulate inflammation, host-defense functions and fibroblast crosstalk in normal and diabetic wound
tissue.

## Key facts

- **NIH application ID:** 10128451
- **Project number:** 5R01DK124290-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Katherine Ann Gallagher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,549
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128451

## Citation

> US National Institutes of Health, RePORTER application 10128451, Epigenetic Regulation of Prostaglandin E2 (PGE2) Synthesis Alters Macrophage Function to Promote Inflammation and Impair Diabetic Wound Healing (5R01DK124290-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10128451. Licensed CC0.

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