Macrophage Phenotype Differentiation in the Rat Uterus during Normal and Diabetic Pregnancies
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Macrophages are the most common type of immune cell in the pregnant uterus. Depending on the tissue microenvironment, macrophages assume one of two broad phenotypes. In general, M1 macrophages destroy extracellular pathogens and present their antigens to cells of the innate immune system. When all invaders have been destroyed, M2 macrophages remove apoptotic cells, remodel tissue, and suppress further inflammation. But which phenotypes predominate at different stages of pregnancy? In this study, macrophage phenotype in the uterus in normal pregnancy was characterized using a rat model. The ratio of M1 to M2 macrophages was estimated at two crucial stages of pregnancy (the first day after mating, and the twelfth day of pregnancy, which is a critical period for embryonic organogenesis) using immunohistochemical labelling. Immunohistochemical staining suggested that M1 macrophages predominate in the uterus right after mating. M2 macrophages are in the minority in the postmating uterus, but predominate on day 12 at the close of the period of organogenesis. This may be because factors in semen induce a transient inflammatory response that is suppressed before embryos enter the uterine horn. So while mating is an M1 phenomenon, during trophoblast invasion, vascular remodeling, implantation and placentation, M2 macrophages prevail. Their role may be to suppress inflammation, to help in vascular remodeling and to clean up apoptotic cells. In pregnancies complicated by diabetes, embryonic abnormalities are common, possibly because the balance of the controls of macrophage phenotype is disturbed. Maternal metabolism was perturbed by injecting pregnant rats with streptozotocin (STZ, induces Type-I diabetes), and its effect on pro-inflammatory macrophages during the period of embryonic organogenesis was studied. Immunohistochemical labeling revealed an increase in M1 levels for the STZ treated dams. Products secreted by M1 macrophages during organogenesis in diabetic pregnancies have been shown to decrease teratogenesis, hence the role of M1 macrophages in diabetic pregnancies could be an ameliorating one.