The physiological role of macrophages in reproductive organs

Abstract

Background: Macrophages are essential immune cells critical to reproductive physiology. They regulate key processes such as follicular development, ovulation, and luteinization in the ovaries. Macrophages are also involved in endometrial remodeling, immune tolerance, and placentation in the uterus.

Methods: This review examined the biological characteristics of macrophages and their role in ovarian, uterine, and fallopian tube physiology. It focused on findings from both animal and human studies to provide a comprehensive understanding of macrophage functions.

Main findings: In the ovaries, M1 macrophages play a role in folliculogenesis and ovulation through the inflammatory and angiogenic pathways. Macrophages also maintain the corpus luteum and vascular integrity. In the uterus, macrophages regulate tissue repair and remodeling during the menstrual cycle and play a critical role in implantation by maintaining immune tolerance and supporting decidualization. Dysregulation of the M1/M2 balance can cause implantation failure. In the fallopian tubes, macrophages mediate tissue repair and immune responses. Macrophage polarization dynamically adapts to physiological and pathological conditions in all reproductive organs highlighting the functional plasticity of these cells.

Conclusion: Macrophage polarization and functions are pivotal in maintaining reproductive health. Hence, understanding the role of macrophages in various reproductive organs provides a foundation for developing new therapies.

Keywords: macrophages; ovaries; reproductive physiology; uterus.

FIGURE 1

Phenotypes of follicular development observed in various DTR mice. Phenotypes of ①CD11b DTR mice, pan (M1 + M2) macrophage depletion model ②CD206 DTR mice, M2 macrophage depletion model ③CD11c DTR mice, M1 macrophage and dendric cell depletion model. In CD11b and CD11c DTR mice, follicular arrest with hemorrhage was observed.

FIGURE 2

Interaction between pericytes and endothelial cells for maintaining vascular integrity. M1 macrophages produce the angiogenic factor PDGF‐B which mobilizes pericytes through PDGF‐Rβ signaling. Both pericytes and endothelial cells are embedded within the basement membrane of microvessels. In the absence of M1 macrophages, the interaction between pericytes and endothelial cells is disrupted leading to vascular instability and hemorrhage.

FIGURE 3

Impact of M2 macrophage depletion on uterine implantation and decidualization. In CD206 DTR mice lacking M2 macrophages, no implantation sites were observed in the uterus (lower panel). Compared to wild‐type mice (upper panel), CD206 DTR mice exhibited impaired decidualization of endometrial stromal cells.

FIGURE 4

The mechanism of impaired implantation in M2 macrophage depleted mouse. Depletion of M2 macrophages suppressed the leukemia inhibitory factor (LIF)‐JAK‐STAT3 pathway. M2 macrophages induced regulatory T cells (Treg), and Treg depletion reduced IL‐10 disrupting immune tolerance. The absence of M2 macrophages led to an excessive increase in M1 macrophages inducing abnormal TNF‐α expression and activating the WNT‐β‐catenin pathway in the uterine epithelium.