Epigenetic Regulation of the COX-2 Pathway Modulates Macrophage Inflammation in Diabetic Wound Repair

Abstract Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to proliferative phase of healing. In pathologic conditions, such as type 2 diabetes (T2D), wounds fail to heal due to impaired resolution of inflammation. There is increasing evidence that epigenetic-based mechanisms control macrophage function. The cyclooxygenase (COX)-2/Prostaglandin E2 (PGE2) axis, as well as upstream pathways including cytosolic phospholipase A2 (c(PL)A2), have been associated with chronic inflammation, however the underlying mechanisms of COX-2/PGE2 regulation in wound repair have not been examined. Here, we find in human and murine diabetic wounds, that PGE2 production is elevated in wound macrophages and regulates inflammation. Further, epigenetic modification of the COX-2/PGE2 pathway was regulated by MLL1, a methyltransferase, that increased H3K4 trimethylation on the cPLA2 promoter in diabetic wound macrophages and human T2D monocytes resulting in increased cPLA2 expression. Myeloid-specific deletion of MLL1 restored basal cPLA2 levels. Separately, increased TGFβ1 in diabetic wounds augmented miR-29b and DNMT 3a/3b in wound macrophages, resulting in hypomethylation of the Cox-2 gene promoter and overexpression of COX-2/PGE2. Inhibition of the PGE2 pathway, with a macrophage-specific nanocarrier containing a COX-2 inhibitor improved diabetic healing. Taken together, our results indicate the COX-2/PGE2 pathway is a critical regulator of macrophage-mediated inflammation in diabetic wounds and therapeutic manipulation of this pathway improves pathologic wound repair.