# Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $569,019

## Abstract

Summary
Infections caused by Staphylococcus aureus are more frequent and severe in people with both type 1 diabetes
(T1D) and T2D than in healthy individuals. For over a century, it has been suggested that phagocytes from
people with diabetes show poor antimicrobial functions, which created the paradigm that diabetes leads to
immunosuppression. However, hyperglycemia also drives an excessive production of inflammatory mediators
by immune cells. Here, we will take our current knowledge in host defense and diabetes in a different direction.
We speculated that increased susceptibility to infection is due to an uncontrolled localized inflammatory response
that causes skin damage and prevents bacterial elimination. We recently showed that S. aureus skin infection in
diabetic mice was accompanied by unrestrained neutrophil migration to the site of infection, increased the
production of inflammatory mediators, poor abscess formation (a structure that prevents spread to deeper tissues
and systemic infection) and impaired bacterial clearance. We also showed inadequate production of the
pleiotropic lipid mediator prostaglandin E2 (PGE2) in the skin of infected diabetic mice and a topical ointment
containing misoprostol (an FDA-approved PGE analog) restored bacterial clearance during diabetes. Our
preliminary data reveal low PGE2 production could be due to a reduced capacity to phagocytes to ingest and
clear dead cells (efferocytosis), leading to secondary necrosis, leakage of endogenous inflammatory mediators,
tissue injury and poor host defense. We are hypothesizing that deficient efferocytosis during MRSA skin infection
in diabetic mice is responsible for low PGE2 production, which increases inflammation-associated tissue damage
and prevents wound healing to ultimately enhance susceptibility to non-healing skin infections. We will utilize
transgenic mice producing constitutively PGE2 and fluorescent phagocytes, along with state-of-the-art
techniques, including imaging mass spectrometry (IMS), in vivo imaging (IVIS) and intravital microscopy imaging
(IVM) to unveil the role of PGE2 levels, the E prostanoid receptors and downstream effectors in tissue repair
during skin infection in people and mice with diabetes (Aim 1). Next, we are postulating that misoprostol
improves wound healing in the infected skin by increasing the production of actions of the second messenger
cyclic adenosine monophosphate (cAMP) downstream effectors involved in misoprostol-improved host defense
in diabetic mice (Aim 2). In the Aim 3, we will study whether the failure of a repair mechanism involved in the
elimination of dead cells (efferocytosis) leads to deficient PGE2 production and generation of inflammatory
mediators, causing tissue injury in the infected skin of diabetic mice. Our project could rapidly translate into
clinical use to improve the treatment of skin infection in patients with diabetes. With antimicrobial resistance and
increasing prevalence of diabetes worldwide,...

## Key facts

- **NIH application ID:** 10136593
- **Project number:** 5R01DK122147-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** C. Henrique Serezani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $569,019
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136593

## Citation

> US National Institutes of Health, RePORTER application 10136593, Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice (5R01DK122147-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136593. Licensed CC0.

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