Multidose Streptozotocin Induction of Diabetes in BALB/c Mice Induces a Dominant Oxidative Macrophage and a Conversion of T(H)1 to T(H)2 Phenotypes During Disease Progression

Macrophages (Mp) are implicated in both early and late phases in type 1 diabetes development. Recent study has suggested that a balance between reductive Mp (RMp) and oxidative Mp (OMp) is possible to regulate T(H)1/T(H)2 balance. The aim of this study is to investigate the redox status of peritoneal Mp and its cytokine profile during the development of autoimmune diabetes induced by multiple low-dose streptozotocin in BALB/c mice. Meanwhile, the polarization of T(H)1/T(H)2 of splenocytes or thymocytes was also examined. We found that peritoneal Mp appeared as an “incomplete” OMp phenotype with decreased icGSH along with disease progression. The OMp showed reduced TNF-α, IL-12, and NO production as well as defective phagocytosis activity compared to nondiabetic controls; however, there was no significant difference with IL-6 production. On the other hand, the levels of IFN-γ or IL-4 of splenocytes in diabetic mice were significantly higher compared to the control mice. The ratio of IFN-γ to IL-4 was also higher at the early stage of diabetes and then declined several weeks later after the occurrence of diabetes, suggesting a pathogenetic T(H)1 phenotype from the beginning gradually to a tendency of T(H)2 during the development of diabetes. Our results implied that likely OMp may be relevant in the development of type 1 diabetes; however, it is not likely the only factor regulating the T(H)1(H)/T(H)2 balance in MLD-STZ-induced diabetic mice.