| First Author | Davis FM | Year | 2020 |
| Journal | J Immunol | Volume | 204 |
| Issue | 9 | Pages | 2503-2513 |
| PubMed ID | 32205424 | Mgi Jnum | J:288516 |
| Mgi Id | MGI:6432202 | Doi | 10.4049/jimmunol.1901263 |
| Citation | Davis FM, et al. (2020) Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair. J Immunol 204(9):2503-2513 |
| abstractText | 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 (Mll1(f/f)Lyz2(Cre+) ), we determined that MLL1 drives Tlr4 expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the Tlr4 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 Tlr4 (Tlr4(-/-) ) or myeloid-specific Tlr4 (Tlr4(f/f)Lyz2(Cre+)) 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. |
