Monocytes and macrophages in pregnancy and pre-eclampsia

Abstract

Preeclampsia is an important complication in pregnancy, characterized by hypertension and proteinuria in the second half of pregnancy. Generalized activation of the inflammatory response is thought to play a role in the pathogenesis of pre-eclampsia. Monocytes may play a central role in this inflammatory response. Monocytes are short lived cells that mature in the circulation and invade into tissues upon an inflammatory stimulus and develop into macrophages. Macrophages are abundantly present in the endometrium and play a role in implantation and placentation in normal pregnancy. In pre-eclampsia, these macrophages appear to be present in larger numbers and are also activated. In the present review, we focused on the role of monocytes and macrophages in the pathophysiology of pre-eclampsia.

Keywords: decidua; macrophages; monocytes; placenta; pre-eclampsia; pregnancy.

Figure 1

Schematic overview of the placenta. The placenta consists of a fetal part and a maternal part. In the fetal part of the placenta, chorionic villi, covered with syncytiotrophoblast, bath in maternal blood of the intervillous space. Direct or indirect contact (via soluble factors) of monocytes with the syncytiotrophoblast may results in monocyte activation. The maternal part of the placenta consists of decidua in which remodeled spiral arteries are present, which take maternal blood to the intervillous space. In the decidua fetal trophoblast, and maternal macrophages and NK cells are present and necessary for immune regulation and spiral artery remodeling ©ilusjessy – Fotolia.com.

Figure 2

Schematic overview of the role of monocytes during healthy pregnancy (A) and pre-eclampsia (B). During healthy pregnancy, placental factors (1) activate monocytes (2) and may affect endothelial cells (2) and induce increased maturation of classical monocytes toward non-classical monocytes (3). During pre-eclampsia, more and other soluble factors are produced from the stressed placenta (1), resulting in further activation of monocytes and endothelial cells (2) and further maturation of classical monocytes toward non-classical monocytes (3). Numbers non-classical monocytes are increased and they may play an important role in this inflammatory process, since they are known to produce increased numbers of cytokines upon activation (4). These cytokines further activate the monocytes (5) as well as endothelial cells (5). This vicious circle of activation of monocytes and endothelial cells finally results in the symptoms of pre-eclampsia, such as hypertension and proteinuria.

Figure 3

Schematic overview of the role of decidual macrophages in pregnancy (A) and pre-eclampsia (B). During normal pregnancy, M2-like macrophages are present around spiral arteries and play a role in remodeling of these arteries by producing various factors associated with angiogenesis and tissue remodeling (such as MMP and VEGF). They also play a role in immunomodulation, for instance by producing IL-10. During pre-eclampsia, increased numbers of M1-like macrophages are found. They may produce pro-inflammatory cytokines, such as TNFα, IL-1β, or IL-18.

Figure 4

Summary of monocytes and macrophages in pregnancy and pre-eclampsia. In healthy pregnancy, soluble factors from the villous trophoblast activate circulating monocytes, induce maturation of classical monocytes toward non-classical monocytes and affect endothelial cells. Non-classical monocytes will invade into the decidua to become M2-like macrophages to support healthy placentation and immunomodulation. During pre-eclampsia, decreased remodeling of the spiral arteries will results in a stressed placenta, which produces increased amounts or different soluble factors as compared with healthy pregnancy. The soluble factors will further activate the monocytes, induce further maturation of classical monocytes toward non-classical monocytes and activate endothelial cells. Activated monocytes, by f.i. producing cytokines, further affect monocytes and endothelial cells. This vicious circle of monocyte and endothelial cell activation results in the maternal symptoms of pre-eclampsia, i.e., hypertension and proteinuria. Moreover, activated classical and non-classical monocytes may invade into the decidua to develop into M1-like and M2-like macrophages, resulting in increased numbers of M1-like macrophages in the pre-eclamptic decidua. The M1-like macrophages may affect the spiral arteries resulting in f.i. acute atherosis, thereby further affecting the placental blood circulation.