Cutting edge: the regulatory mechanisms of macrophage polarization and function during pregnancy

Macrophages are highly diverse cells and represent the major antigen-presenting cell at the maternal-fetal interface. Except for protecting the embryo with half of the paternal antigens from attack by the maternal immune system, decidua macrophages also have a critical role in implantation, trophoblast invasion, spiral artery remodeling, angiogenesis, and pathogen clearance. The classically activated (M1) and alternatively activated (M2) macrophages are the simplified classifications of macrophages, often applied to differentiate decidual macrophages. Particular phenotypes and functions of macrophages corresponding to each phase of the menstrual cycle and pregnancy are critical for establishing and maintaining pregnancy. Aberrant dynamics of decidual macrophages are associated with multiple pregnancy complications, such as recurrent pregnancy loss, preeclampsia, and preterm birth. Although various factors are related to decidual macrophage polarization, including cytokines, growth factors, hormones, and transcription factors, the potential regulatory mechanisms underlying decidual macrophage polarization are still unclear. Therefore, a thorough understanding of macrophage function and regulatory mechanism during pregnancy is critical to clarify the pathogenesis of pregnancy complications. In this review, we first describe an overview of the origin, phenotype, and function of macrophages in the uterus. Secondly, we propose emerging concepts explaining how macrophage polarization and functions are regulated, including immunometabolism, epigenetics, immune checkpoint, and microorganisms. Finally, we review the potential relationship among these novel factors in regulating the function of the immune system.