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TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF
Aaron D. denDekker, … , Steven L. Kunkel, Katherine A. Gallagher
Aaron D. denDekker, … , Steven L. Kunkel, Katherine A. Gallagher
Published February 18, 2020
Citation Information: JCI Insight. 2020;5(5):e132306. https://doi.org/10.1172/jci.insight.132306.
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Research Article Immunology Inflammation

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF

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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 Moffl/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.

Authors

Aaron D. denDekker, Frank M. Davis, Amrita D. Joshi, Sonya J. Wolf, Ronald Allen, Jay Lipinski, Brenda Nguyen, Joseph Kirma, Dylan Nycz, Jennifer Bermick, Bethany B. Moore, Johann E. Gudjonsson, Steven L. Kunkel, Katherine A. Gallagher

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Figure 1

MOF regulates macrophage function during wound healing.

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MOF regulates macrophage function during wound healing.
(A) Representati...
(A) Representative figure showing Mof expression in wounds over time. Three wounds were created using a 6-mm punch on the backs of WT C57BL/6J mice. Wound macrophages (CD11b+CD3–CD19–Ly6G–) were isolated at baseline (day 0) and on days 1, 3, 5, and 7 after injury, and Mof gene expression was assessed (n = 3 × 3 mice pooled/replicate/time point; repeated twice). Data were analyzed for normality and 1-way ANOVA was performed followed by Tukey’s multiple-comparisons test. (B) Representative figures of Msl1 and Kansl1 expression in day 5 wounds. Wound macrophages (CD11b+CD3–CD19–Ly6G–) were isolated on days 1 and 5 after injury. Msl1 and Kansl1 gene expression were measured by quantitative PCR (qPCR) (n = 3 × 3 mice pooled/replicate/time point; repeated twice). Data were analyzed for normality and 2-tailed Student’s t test was performed. (C) Representative figure showing divergence in Mof expression between cell types in day 5 wounds. Macrophages (CD11b+CD3–CD19–Ly6G–, n = 4), neutrophils (CD11b+CD3–CD19–Ly6G+, n = 3), and combined T/B cells (CD3+/CD19+CD11b–Ly6G–, n = 3) were isolated on 5 after wounding. Mof gene expression was measured by qPCR (n = 3 mice pooled/replicate/time point; repeated twice). Data were analyzed using 1-way ANOVA followed by Tukey’s test for multiple comparisons.
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