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

University Of Michigan At Ann Arbor, Ann Arbor MI

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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 (M?) transitions from an inflammatory phenotype, which is prone to tissue destruction, to a reparative cell. In T2D, inflammatory M?s 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 M?s 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)?1 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 TGF?1 in T2D M?s leads to increased COX-2 expression and PGE2 production, and that targeted therapy will reverse these processes leading to decreased pro-inflammatory M?s and improved wound healing. This hypothesis will be investigated through the following specific aims: 1) Elucidate the TLR4-mediated regulation of M?-specific COX-2 expression in normal and diabetic wounds. We will also test the therapeutic efficacy of TLR4 antagonists in vivo. 2) Investigate the TGF?1-induced miR-29b/DNA methyltransferase regulation of COX-2 expression in normal and diabetic wound M?s and evaluate the therapeutic efficacy of local TGF? receptor antagonists and COX-2 inhibitors targeted to wound M?s.