Kimball Andrew S, Joshi Amrita, Carson William F, Boniakowski Anna E, Schaller Matthew, Allen Ronald, Bermick Jennifer, Davis Frank M, Henke Peter K, Burant Charles F, Kunkel Steve L, Gallagher Katherine A
Department of Surgery, University of Michigan, Ann Arbor, MI.
Department of Pathology, University of Michigan, Ann Arbor, MI.
Diabetes. 2017 Sep;66(9):2459-2471. doi: 10.2337/db17-0194. Epub 2017 Jun 29.
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-κB (NF-κB)-mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific knockout ( ) to determine the function of MLL1 in wound healing. mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB 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 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.
巨噬细胞对于伤口修复炎症阶段的启动和消退至关重要。在糖尿病患者中，巨噬细胞在伤口愈合后期呈现出延长的炎症表型。混合谱系白血病-1（MLL1）已被证明可通过调节核因子-κB（NF-κB）介导的炎症基因转录来指导基因表达。因此，我们推测MLL1在伤口修复中影响巨噬细胞介导的炎症。我们使用髓系特异性敲除（ ）来确定MLL1在伤口愈合中的功能。与对照动物相比， 小鼠伤口愈合延迟，伤口巨噬细胞炎症细胞因子产生减少。此外，来自 小鼠的伤口巨噬细胞在炎症基因启动子上的NF-κB结合位点处显示组蛋白H3赖氨酸4三甲基化（H3K4me3）（激活标记）减少。值得注意的是，与对照组相比，糖尿病前期小鼠的早期伤口巨噬细胞在炎症基因启动子处的MLL1、H3K4me3和炎症细胞因子同样减少。糖尿病前期小鼠的晚期伤口巨噬细胞在炎症基因启动子处的MLL1、H3K4me3和炎症细胞因子增加。用MLL1抑制剂处理的糖尿病前期巨噬细胞炎症减轻。最后，2型糖尿病患者的单核细胞与无糖尿病的对照受试者相比 增加。这些结果确定了MLL1在调节伤口修复中巨噬细胞介导的炎症中的重要作用，并确定了治疗糖尿病伤口慢性炎症的潜在靶点。
