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

• DOI: 10.1172/jci.insight.138443
• Publication Date: 2020-09-02T15:01:28Z
• Authors: Frank M. Davis; Lam C. Tsoi; Rachael Wasikowski; Aaron denDekker; Amrita Joshi; Carol Wilke; Hongping Deng; Sonya Wolf; Andrea Obi; Steven Huang; Allison C. Billi; Scott Robinson; Jay Lipinski; William J. Melvin; Christopher O. Audu; Stephan Weidinger; Steven L. Kunkel; Andrew Smith; Johann E. Gudjonsson; Bethany B. Moore; Katherine A. Gall...
• Keywords: Male; 0301 basic medicine; Dinoprostone; Diabetes Mellitus, Experimental; Epigenesis, Genetic; Mice; 03 medical and health sciences; Endocrinology; Oxytocics; Diabetes Mellitus; Animals; Humans; Aged; Inflammation; Mice, Knockout; Macrophages; R; NF-kappa B; 3. Good health; Mice, Inbred C57BL; Phenotype; Gene Expression Regulation; Cyclooxygenase 2; Pseudomonas aeruginosa; Medicine; Research Article; Signal Transduction

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