Journal article
The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes
Diabetes (New York, N.Y.), Vol.66(9), pp.2459-2471
09/01/2017
DOI: 10.2337/db17-0194
PMCID: PMC5566299
PMID: 28663191
Abstract
Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-kappa B (NF-kappa B)-mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific Mll1 knockout (Mll1(f/f)Lyz2(Cre+)) to determine the function of MLL1 in wound healing. Mll1(f/f)Lyz2(Cre+) mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from Mll1(f/f)Lyz2(Cre+) mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-kappa B binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased Mll1 compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds.
Details
- Title: Subtitle
- The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes
- Creators
- Andrew S. Kimball - University of Michigan–Ann ArborAmrita Joshi - University of Michigan–Ann ArborWilliam F. Carson - University of Michigan–Ann ArborAnna E. Boniakowski - University of Michigan–Ann ArborMatthew Schaller - University of Michigan–Ann ArborRonald Allen - University of Michigan–Ann ArborJennifer Bermick - University of Michigan–Ann ArborFrank M. Davis - University of Michigan–Ann ArborPeter K. Henke - University of Michigan–Ann ArborCharles F. Burant - University of Michigan–Ann ArborSteve L. Kunkel - University of Michigan–Ann ArborKatherine A. Gallagher - University of Michigan–Ann Arbor
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.66(9), pp.2459-2471
- Publisher
- Amer Diabetes Assoc
- DOI
- 10.2337/db17-0194
- PMID
- 28663191
- PMCID
- PMC5566299
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Number of pages
- 13
- Grant note
- DK-102357; T32-HL076123 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32HL076123 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) K08DK102357 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Taubman Scholars Foundation
- Language
- English
- Date published
- 09/01/2017
- Academic Unit
- Stead Family Department of Pediatrics; Neonatology
- Record Identifier
- 9984354156202771
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