Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
J Cell Physiol. 2012 Apr;227(4):1670-9. doi: 10.1002/jcp.22891.
Abnormal immunity and its related complications are the major causes of mortality and morbidity in diabetes patients. Macrophages, as one of the important innate cells, play pivotal roles in controlling immune homeostasis, immunity, and tolerance. The effects of hyperglycemia on the function of macrophages in hosts remain to be determined. Here we used mice with streptozotocin (STZ)-induced diabetes for long term to study the changes of macrophages. We found that F4/80(+) peritoneal exudate macrophages (PEMs) from mice with diabetes for 4 months displayed significantly reduced CD86 and CD54 expression and tumor necrosis factor (TNF)-α and IL-6 production but enhanced nitric oxide (NO) secretion compared with control mice when treated with interferon (IFN)-γ and lipopolysaccharide (LPS), while the activity of arginase in PEMs from diabetic mice was significantly higher than control mice when stimulating with IL-4. These dysfunctions of macrophages could be efficiently reversed by insulin treatment. Importantly, in vitro bone marrow-derived macrophages showed similar functional changes, indicating the epigenetic alteration of macrophage precursors in these mice. In an in vitro culture system, high glucose and insulin significantly altered TNF-α, IL-6, and NO production and arginase activity of macrophages, which was reversed by the treatment with AKT and ERK inhibitors. Therefore, hyperglycemia and insulin deficiency can modify macrophage function through AKT-mTOR and ERK pathways and through epigenetic effects on macrophage precursors. To further identify different components of diabetes on the dysfunction of macrophages is important for efficient prevention of diabetic complications.
异常的免疫反应及其相关并发症是糖尿病患者死亡和发病的主要原因。巨噬细胞作为重要的先天细胞之一，在控制免疫稳态、免疫和耐受方面发挥着关键作用。高血糖对宿主巨噬细胞功能的影响仍有待确定。在这里，我们使用链脲佐菌素（STZ）诱导的糖尿病小鼠进行长期研究，以研究巨噬细胞的变化。我们发现，糖尿病 4 个月的小鼠腹膜渗出液巨噬细胞（PEM）中 CD86 和 CD54 的表达以及肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6 的产生明显降低，而当用干扰素（IFN）-γ和脂多糖（LPS）处理时，NO 的分泌明显增强，而 IL-4 刺激时糖尿病小鼠 PEM 中的精氨酸酶活性明显高于对照组。这些巨噬细胞的功能障碍可以通过胰岛素治疗得到有效逆转。重要的是，体外骨髓来源的巨噬细胞表现出相似的功能变化，表明这些小鼠中巨噬细胞前体的表观遗传改变。在体外培养系统中，高葡萄糖和胰岛素显著改变了巨噬细胞 TNF-α、IL-6 和 NO 的产生以及精氨酸酶的活性，而 AKT 和 ERK 抑制剂的处理则逆转了这种变化。因此，高血糖和胰岛素缺乏可以通过 AKT-mTOR 和 ERK 途径以及对巨噬细胞前体的表观遗传作用来改变巨噬细胞的功能。进一步确定糖尿病的不同成分对巨噬细胞功能障碍的影响对于有效预防糖尿病并发症非常重要。
