A Hypoxia-Decidual Macrophage Regulatory Axis in Normal Pregnancy and Spontaneous Miscarriage

Abstract

The significance of hypoxia at the maternal-fetal interface is proven to be self-explanatory in the context of pregnancy. During the first trimester, low oxygen conditions play a crucial role in processes such as angiogenesis, trophoblast invasion and differentiation, and immune regulation. Recently, there has been increasing research on decidual macrophages, which contribute to the maintenance of immune tolerance, placental and fetal vascular development, and spiral artery remodeling, to investigate the effects of hypoxia on their biological behaviors. On these grounds, this review describes the dynamic changes in oxygen levels at the maternal-fetal interface throughout gestation, summarizing current knowledge on how the hypoxic environment sustains a successful pregnancy by regulating retention, differentiation and efferocytosis of decidual macrophages. Additionally, we explore the relationship between spontaneous miscarriages and an abnormal hypoxia-macrophage axis, shedding light on the underlying mechanisms. However, further studies are essential to elucidate these pathways in greater detail and to develop targeted interventions that could improve pregnancy outcomes.

Keywords: abortion; decidual macrophage; hypoxia; polarization; retention.

Figure 1

At the maternal–fetal interface, numerous macrophages can be recruited from the peripheral circulation to the decidua under hypoxia. Once recruited, macrophages are retained in the decidua through various adhesion molecules, including ICAM1, ICAM2, ICAM5, and CLDN7.

Figure 2

Fluctuations in oxygen levels at the maternal-fetal interface modulate the residency, polarization, and efferocytosis of dMφs, contributing to different pregnancy outcomes. In spontaneous abortion, severe hypoxia (1% O₂) at the maternal-fetal interface promotes excessive secretion of CCL2 by dMφs, leading to the overaccumulation of dMφs, particularly of the pro-inflammatory M1 subtype. Moreover, the IL-33/ST2 signaling axis is disrupted in dMφs during spontaneous abortion, with elevated sST2 levels exacerbating this imbalance, ultimately driving enhanced efferocytosis.