The Mac Is Back: The Role of Macrophages in Human Healthy and Complicated Pregnancies

Abstract

Pregnancy is a fascinating immunological paradox: the semi-allogeneic fetus generally grows without any complications. In the placenta, fetal trophoblast cells come into contact with maternal immune cells. Inaccurate or inadequate adaptations of the maternal immune system could lead to problems with the functioning of the placenta. Macrophages are important for tissue homeostasis, cleanup, and the repair of damaged tissues. This is crucial for a rapidly developing organ such as the placenta. The consensus on macrophages at the maternal-fetal interface in pregnancy is that a major proportion have an anti-inflammatory, M2-like phenotype, that expresses scavenger receptors and is involved in tissue remodeling and the dampening of the immune reactions. Recent multidimensional analyses have contributed to a more detailed outlook on macrophages. The new view is that this lineage represents a highly diverse phenotype and is more prevalent than previously thought. Spatial-temporal in situ analyses during gestation have identified unique interactions of macrophages both with trophoblasts and with T cells at different trimesters of pregnancy. Here, we elaborate on the role of macrophages during early human pregnancy and at later gestation. Their possible effect is reviewed in the context of HLA incompatibility between mother and fetus, first in naturally conceived pregnancies, but foremost in pregnancies after oocyte donation. The potential functional consequences of macrophages for pregnancy-related immune reactions and the outcome in patients with recurrent pregnancy loss are also discussed.

Pregnancies through oocyte donation. A mini review of pathways involved in placental dysfunction

“…Normal placentation and pregnancy evolution requires the development of maternal immune tolerance to a semi-allogeneic fetus. To date, most accepted mechanisms involved in pregnancy immunomodulation and crosstalk between mother and fetus include; (i) a trophoblast with an overall poor antigenicity, mainly due to a lack of classic HLA-I and II antigens, with the exception of HLA-C, and the expression of nonclassical HLA molecules of class E and G ( 97 , 98 ); (ii) a shift in the functional balance of T helper (Th) cells towards type-2 cells with a decline in cell-mediated Th1-type immunity ( 99 ); (iii) a change in the activity of uterine natural killer (uNK) cells from cytotoxic to regulatory, mainly producing chemokines, growth factors, cytokines and angiogenic factors, of relevance for the development of maternal–fetal interface ( 100 ); and (iv) a major proportion of macrophages with an anti-inflammatory, M2-like phenotype, involved in the dampening of immune reactions ( 98 ).…”

The Ferritin, Hepcidin and Cytokines Link in the Diagnoses of Iron Deficiency Anaemia during Pregnancy: A Review

“…Based on their function and cytokine production profile, macrophages are classified as M1 or M2 phenotype [57]. The M1 phenotype is proinflammatory and produces pro-inflammatory cytokines such as IL-6, IL-12 and TNF-α, whereas M2 is anti-inflammatory and produces anti-inflammatory cytokines such as IL-4, IL-10 and TGF-β [58]. In healthy pregnancy, the majority of macrophages on the maternalfoetal interface are of the M2 phenotype.…”