Department of Surgery.
Department of Pathology.
JCI Insight. 2020 Mar 12;5(5):132306. doi: 10.1172/jci.insight.132306.
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.
伤口愈合的一个关键组成部分是从炎症期过渡到增殖期，以启动伤口的愈合和重塑。巨噬细胞在伤口修复过程中对炎症期的启动和解决至关重要。在糖尿病中，巨噬细胞在晚期伤口愈合中表现出持续的炎症表型，其特征是炎症细胞因子（如 TNF-α）的产生增加。先前的研究表明，改变的表观遗传程序指导糖尿病巨噬细胞向促炎表型发展，导致持续的炎症期。缺失在第一染色体上的雄性（Male absent on the first，MOF）是一种组蛋白乙酰转移酶（histone acetyltransferase，HAT），已被证明是 TNF-α 信号的共激活因子，并促进前列腺癌细胞系中 NF-κB 介导的基因转录。基于 MOF 在 TNF-α/NF-κB 介导的基因表达中的作用，我们假设 MOF 会影响伤口修复过程中巨噬细胞介导的炎症。我们使用髓系特异性 Mof 敲除（Lyz2Cre Moffl/fl）和饮食诱导肥胖（diet-induced obese，DIO）小鼠来确定 MOF 在糖尿病伤口愈合中的功能。MOF 缺陷小鼠表现出炎症细胞因子基因表达减少。此外，我们发现 DIO 小鼠的伤口巨噬细胞中 MOF 水平升高，以及 MOF 的主要 HAT 活性底物组蛋白 H4K16 的乙酰化水平在炎症基因的启动子上升高。我们进一步确定 MOF 的表达可以被 TNF-α 刺激，并且 FDA 批准的 TNF-α 抑制剂依那西普的治疗可以降低 DIO 小鼠中的 MOF 水平并改善伤口愈合。本报告首次定义了 MOF 在调节伤口修复中巨噬细胞介导的炎症中的重要作用，并确定 TNF-α 抑制作为治疗糖尿病伤口慢性炎症的潜在疗法。
