Abstract
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)βinduced 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)βΞ± and ILβ6 production but enhanced nitric oxide (NO) secretion compared with control mice when treated with interferon (IFN)βΞ³ and lipopolysaccharide (LPS), while the activity of arginase in PEMs from diabetic mice was significantly higher than control mice when stimulating with ILβ4. These dysfunctions of macrophages could be efficiently reversed by insulin treatment. Importantly, in vitro bone marrowβderived 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 TNFβΞ±, ILβ6, 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 AKTβmTOR 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. J. Cell. Physiol. 227: 1670β1679, 2012. Β© 2011 Wiley Periodicals, Inc.