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

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

doi:10.1172/jci.insight.132306

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.

Highlights

The innate immune system plays a fundamental role in the resolution of wounds after injury
We found that Mof was upregulated at both days 3 and 5 after injury during a key transition where macrophages shift from a proinflammatory to an antiinflammatory phenotype (Figure 1A)
We found that both Msl1 and Kansl1 were upregulated in wound macrophages at day 5 after injury, suggesting that Males absent on the first (MOF) may play an important role in the transition to an antiinflammatory phenotype in wounds (Figure 1B)

Summary

Introduction

The innate immune system plays a fundamental role in the resolution of wounds after injury. The inflammatory phase is initiated when peripheral monocytes are recruited to the wound site, where they initially differentiate into proinflammatory macrophages secreting inflammatory cytokines (e.g., IL-1β, TNF-α, and IL-6) [2,3,4]. This phase is critical to clear the wound site of microbes and cellular debris. Sustained inflammation due to the inability of wound macrophages to transition to the regeneration stage necessary for normal skin repair is a hallmark of impaired wound healing associated with diseases such as type 2 diabetes (T2D) [6,7,8,9,10,11]. We have shown that MLL1 and JMJD3; a histone methyltransferase and histone demethylase, respectively, are altered in T2D macrophages, drive production of proinflammatory cytokines, and establish a proinflammatory feedback loop leading to uncontrolled inflammation [12, 14, 16]

Methods

Results

Conclusion