Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10

During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (Mfφ), one of the major leukocyte populations at the fetal-maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual Mφ with an in vitro Mφ differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) Mφ markers expressed on human decidual Mf (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2- dominated environment is not required for decidual Mf polarization. M-CSF/IL-10-stimulated and decidual Mf also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ-stimulated Mφ produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 Mφ-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual Mφ, confirming that M-CSF/IL-10-induced Mφ are closely related to decidual Mφ. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual Mφ with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.