Modulators of the Balance between M1 and M2 Macrophages during Pregnancy

Abstract

Macrophages are a subset of mononuclear phagocytes of the innate immune system with high plasticity and heterogeneity. At the maternal-fetal interface, macrophages are present in all stages of pregnancy and involved in a variety of activities, including regulation of immune cell activities, decidualization, placental cell invasion, angiogenesis, parturition, and postpartum uterine involution. The activation state and function of uterine-placental macrophages are largely dependent on the local tissue microenvironment. However, disruption of the uterine microenvironment can have profound effects on macrophage activity and subsequently impact pregnancy outcome. Thus, appropriately and timely regulated macrophage polarization has been considered a key determinant of successful pregnancy. Targeting macrophage polarization might be an efficient strategy for maintaining maternal-fetal immune homeostasis and a normal pregnancy. Here, we will review the latest findings regarding the modulators regulating macrophage polarization in healthy pregnancies and pregnancy complications, which might provide a basis for macrophage-centered therapeutic strategies.

Keywords: GM-CSF; HLA-G; Tim-3; macrophage; maternal-fetal interface; notch signal; polarization; pregnancy.

Figure 1

Dynamics between M1 and M2 macrophages along pregnancy. During the different phases of gestation, macrophages undergo dynamic changes, predominantly displaying the M1 or M2 phenotype. After coitus, granulocyte macrophage colony-stimulating factor levels are increased by transforming growth factor beta (TGF-β) in the seminal fluid and promote M1 activation. In the peri-implantation period, activated M1 macrophages produce inflammatory cytokines and mediators, such as interleukin (IL)-6, IL-1β, tumor necrosis factor alpha, and nitric oxide, inducing pro-inflammatory responses and promoting embryo attachment to the decidua. As the trophoblast invades the uterine stroma, decidual macrophages initiate an M1/M2 profile until the early phase of the second trimester of pregnancy, displaying both the pro- and anti-inflammatory phenotype, which endows the host with the ability to promote trophoblast invasion and vascular remodeling and prevent rejection of the embryo. Subsequently, in order to allow fetal development, more progesterone is produced, and an M2-dominant environment is established in the uterus until the end of pregnancy, which includes downregulation of inflammatory mediators, increased generation of anti-inflammatory cytokines (e.g., IL-10 and TGF-β), and phagocytosis of apoptotic debris. Finally, M1 macrophages predominate over the M2 subset again during the period of parturition, which is considered an inflammatory event. Accumulated M1 macrophages promote the contraction of the uterus, expulsion of the baby, ejection of the placenta and uterine involution.

Figure 2

Essential modulators of macrophage polarization during pregnancy. Under inflammatory conditions, bone marrow-derived monocytes contribute to tissue macrophage homeostasis. As previously mentioned, M-CSF, estrogen, HCG, HLA-G5, hAMSC, Tim-3, and FR-β promote the polarization toward M2 macrophages (blue point arrows) and inhibit M1 polarization (blue block arrows). GM-CSF, Notch signaling, and diabetes/hyperglycemia have been implicated in the polarization of M1 macrophages (red point arrows), while suppressing M2 macrophage polarization (red block arrows). Whether Toxoplasma gondii facilitates M1 or M2 macrophage polarization is uncertain (dashed green arrows), and it mainly depends on the host immune status and the virulence of the pathogen. M-CSF, macrophage colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HCG, human chorionic gonadotropin; HLA-G, human leukocyte antigen G; hAMSC, human amniotic mesenchymal stem cell; Tim-3, T-cell Ig and mucin domain protein 3; FR-β, folate receptor β.