Notch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing.
Notch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing.
复制标题
DOI：
10.3389/fimmu.2017.00635
复制
发表时间：
2017
影响因子：
7.3
通讯作者：
Gallagher KA
中科院分区：
文献类型：
--
作者：
Kimball AS;Joshi AD;Boniakowski AE;Schaller M;Chung J;Allen R;Bermick J;Carson WF 4th;Henke PK;Maillard I;Kunkel SL;Gallagher KA
巨噬细胞是伤口愈合过程中调节炎症所必需的重要免疫细胞。最近的研究发现，Notch 在巨噬细胞介导的炎症中发挥作用。因此，我们研究了 Notch 信号在正常和糖尿病伤口愈合过程中对伤口巨噬细胞表型和功能的作用。我们发现正常愈合过程中伤口巨噬细胞中Notch受体和配体的表达是动态的。具有骨髓特异性Notch信号缺陷（DNMAMLfloxedLyz2Cre+）的小鼠表现出早期愈合延迟（第1-3天），并且伤口巨噬细胞炎症基因表达减少。在我们的 2 型糖尿病 (T2D) 生理性小鼠模型中，伤口巨噬细胞中的 Notch 受体表达在伤口愈合的初始炎症阶段后第 6 天显着增加，这对应于炎症细胞因子表达的增加。 Notch1 和 Notch2 的这种增加也在 T2D 患者的人单核细胞中观察到。此外，在具有遗传性 Notch 信号缺陷的糖尿病前期小鼠（采用高脂肪饮食的 DNMAMLfloxedLyz2Cre+）中，在后期（第 6-7 天）发现伤口愈合有所改善。这些发现表明，Notch 对于伤口愈合的早期炎症阶段至关重要，并指导巨噬细胞依赖性炎症介质的产生。这些结果表明，经典的 Notch 信号传导对于指导巨噬细胞在伤口修复中的功能非常重要，并确定了治疗不愈合糖尿病伤口的转化靶标。
Macrophages are essential immune cells necessary for regulated inflammation during wound healing. Recent studies have identified that Notch plays a role in macrophage-mediated inflammation. Thus, we investigated the role of Notch signaling on wound macrophage phenotype and function during normal and diabetic wound healing. We found that Notch receptor and ligand expression are dynamic in wound macrophages during normal healing. Mice with a myeloid-specific Notch signaling defect (DNMAMLfloxedLyz2Cre+) demonstrated delayed early healing (days 1–3) and wound macrophages had decreased inflammatory gene expression. In our physiologic murine model of type 2 diabetes (T2D), Notch receptor expression was significantly increased in wound macrophages on day 6, following the initial inflammatory phase of wound healing, corresponding to increased inflammatory cytokine expression. This increase in Notch1 and Notch2 was also observed in human monocytes from patients with T2D. Further, in prediabetic mice with a genetic Notch signaling defect (DNMAMLfloxedLyz2Cre+ on a high-fat diet), improved wound healing was seen at late time points (days 6–7). These findings suggest that Notch is critical for the early inflammatory phase of wound healing and directs production of macrophage-dependent inflammatory mediators. These results identify that canonical Notch signaling is important in directing macrophage function in wound repair and define a translational target for the treatment of non-healing diabetic wounds.