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Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair.

Citation
Davis, F. M., et al. “Epigenetic Regulation Of Tlr4 In Diabetic Macrophages Modulates Immunometabolism And Wound Repair.”. Journal Of Immunology (Baltimore, Md. : 1950), pp. 2503-2513.
Center University of Michigan
Featured
Author Frank M Davis, Aaron Dendekker, Andrew Kimball, Amrita D Joshi, Mahmoud El Azzouny, Sonya J Wolf, Andrea T Obi, Jay Lipinski, Johann E Gudjonsson, Xianying Xing, Olesya Plazyo, Christopher Audu, William J Melvin, Kanakadurga Singer, Peter K Henke, Bethany B Moore, Charles Burant, Steven L Kunkel, Katherine A Gallagher
Abstract

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout ( ), we determined that MLL1 drives expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either ( ) or myeloid-specific resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.

Year of Publication
2020
Journal
Journal of immunology (Baltimore, Md. : 1950)
Volume
204
Issue
9
Number of Pages
2503-2513
Date Published
05/2020
ISSN Number
1550-6606
DOI
10.4049/jimmunol.1901263
Alternate Journal
J. Immunol.
PMID
32205424
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