# Toll-like Receptor 4 and Transforming Growth Factor Beta Receptor Stimulation in Macrophages Regulate Prostaglandin-mediated Inflammation and Direct Wound Healing

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $66,916

## 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. Equally concerning, our current “standard of care” leaves 70%
of diabetic wounds unhealed. Given this substantial impact on patient outcomes and healthcare expenditure, a
critical unmet need exists for improved understanding of the pathophysiology of diabetic wounds and to
develop effective treatments. Under normal wound healing conditions, the macrophage (Mφ) transitions from
an inflammatory phenotype, which is prone to tissue destruction, to a reparative cell. In T2D, inflammatory Mφs
fail to transition to the reparative phenotype and the molecular mechanisms behind this are not elucidated;
leaving a large deficit in our ability to prevent and treat these wounds. Using human cells and our experimental
murine models of wound healing, our lab has shown the prostaglandin E2 (PGE2) pathway is persistently
elevated in diabetic wound Mφs and that this leads to impaired wound healing. Prior research by others and
our lab has identified that both toll-like receptor 4 (TLR4) stimulation and increased levels of transforming
growth factor (TGF)β1 are present in diabetic wounds and lead to upregulation of cyclooxygenase-2 (COX-2),
the enzyme necessary for PGE2 production. We hypothesize that upregulation of TLR4 and TGFβ1 in T2D
Mφs leads to increased COX-2 expression and PGE2 production, and that targeted therapy will reverse
these processes leading to decreased pro-inflammatory Mφs and improved wound healing. This
hypothesis will be investigated through the following specific aims: 1) Elucidate the TLR4-mediated regulation
of Mφ-specific COX-2 expression in normal and diabetic wounds. We will also test the therapeutic efficacy of
TLR4 antagonists in vivo. 2) Investigate the TGFβ1-induced miR-29b/DNA methyltransferase regulation of
COX-2 expression in normal and diabetic wound Mφs and evaluate the therapeutic efficacy of local TGFβ
receptor antagonists and COX-2 inhibitors targeted to wound Mφs.

## Key facts

- **NIH application ID:** 10134705
- **Project number:** 1F32HL152508-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** William James Melvin
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,916
- **Award type:** 1
- **Project period:** 2021-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134705

## Citation

> US National Institutes of Health, RePORTER application 10134705, Toll-like Receptor 4 and Transforming Growth Factor Beta Receptor Stimulation in Macrophages Regulate Prostaglandin-mediated Inflammation and Direct Wound Healing (1F32HL152508-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10134705. Licensed CC0.

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