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National Institute of Environmental Health Sciences

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Publication Detail

Title: Epigenetic regulation of the PGE2 pathway modulates macrophage phenotype in normal and pathologic wound repair.

Authors: Davis, Frank M; Tsoi, Lam C; Wasikowski, Rachael; denDekker, Aaron; Joshi, Amrita; Wilke, Carol; Deng, Hongping; Wolf, Sonya; Obi, Andrea; Huang, Steven; Billi, Allison C; Robinson, Scott; Lipinski, Jay; Melvin, William J; Audu, Christopher O; Weidinger, Stephan; Kunkel, Steven L; Smith, Andrew; Gudjonsson, Johann E; Moore, Bethany B; Gallagher, Katherine A

Published In JCI Insight, (2020 09 03)

Abstract: Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.

PubMed ID: 32879137 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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