Journal article
TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF
JCI insight, Vol.5(5), e132306
03/12/2020
DOI: 10.1172/jci.insight.132306
PMCID: PMC7141388
PMID: 32069267
Abstract
A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB–mediated gene transcription in prostate cancer cell lines. Based on MOF’s role in TNF-α/NF-κB–mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific
Mof
-knockout (
Lyz2Cre Mof
fl/fl
) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF’s primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.
TNF-α drives expression of the histone acetyltransferase MOF to promote inflammation in macrophages in nonhealing diabetic wounds.
Details
- Title: Subtitle
- TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF
- Creators
- Aaron D. denDekker - University of MichiganFrank M. Davis - University of MichiganAmrita D. Joshi - University of MichiganSonya J. Wolf - University of MichiganRonald Allen - University of MichiganJay Lipinski - University of MichiganBrenda Nguyen - University of MichiganJoseph Kirma - University of MichiganDylan Nycz - University of MichiganJennifer Bermick - University of MichiganBethany B. Moore - University of MichiganJohann E. Gudjonsson - University of MichiganSteven L. Kunkel - University of MichiganKatherine A. Gallagher - University of Michigan
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.5(5), e132306
- DOI
- 10.1172/jci.insight.132306
- PMID
- 32069267
- PMCID
- PMC7141388
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- HL137919 / NIH NHLBI
- Language
- English
- Date published
- 03/12/2020
- Academic Unit
- Stead Family Department of Pediatrics; Neonatology
- Record Identifier
- 9984354004502771
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