Macrophage and Preeclampsia: Macrophage Polarization Imbalance at the Maternal-Fetal Interface

Abstract

Background: Preeclampsia (PE), as a pathological pregnancy process, is still unclear in its precise pathophysiology. The current consensus on PE pathogenesis is that it is an immune-inflammatory response due to placental dysfunction leading to multiorgan involvement in the mother. Macrophages can polarize into different phenotypes under the influence of distinct microenvironments, secreting various cytokines or chemokines with distinct functions. These phenotypes play roles in either promoting inflammation or facilitating tissue repair. Studies have observed the increase in M1 polarization of decidual macrophages during the occurrence of PE, with this polarization imbalance contributing to the immuno-inflammatory response involved in placental formation. Therefore, understanding the polarization characteristics of macrophages provides a valuable direction for research related to the prevention and treatment of PE.

Methods: Authors searched for related literature on PubMed using the professional terms "preeclampsia" and "macrophage polarization". The obtained literature was categorized according to its research. Similar articles are summarized in the same sections, which are divided into different small sections according to their specific contents.

Results: Different studies have explored the metabolic characteristics, surface markers, secretions, signaling pathways, and functions of different macrophage polarization types, highlighting the critical role of polarization imbalance and excessive inflammatory responses in the development of PE. Intervening in inflammatory responses at the maternal-fetal interface holds significant value for the prevention and treatment of PE.

Conclusion: Understanding the metabolic characteristics of different macrophage polarization types, combined with their polarization imbalance during the development of PE, can facilitate targeted prevention of PE.

Keywords: inflammation; macrophages; polarization; polarization imbalance; preeclampsia.

FIGURE 1

Differences between M1 and M2 macrophages in glucose metabolism, lipid metabolism, and cytokine expression. (1)Macrophages can be stimulated by Lipopolysaccharides(LPS), and then transmit the signal via the MyD88 pathway or TRIF pathway, leading to the NF‐κB‐mediated expression of various pro‐inflammatory cytokines, such as IL‐1β and TNF‐α [43]. In M1 macrophages, Glycolysis is enhanced, the tricarboxylic acid (TCA) cycle is interrupted, and acetyl‐CoA is exported from the mitochondria through the citrate‐pyruvate cycle to participate in lipid synthesis. In addition, the pentose phosphate pathway (PPP) is upregulated, further promoting lipid synthesis [44, 45]. (2)When IL‐4 binds to IL‐4R on the surface of macrophages, signaling is transmitted via the JAK‐STAT6 pathway, resulting in the expression of various anti‐inflammatory cytokines, such as IL‐10 and IL‐12. M2 macrophages maintain an intact oxidative phosphorylation (OXPHOS) axis [19] and can intake lipid through CD36. These lipids are broken down into fatty acids, which enter the TCA cycle to generate energy [44, 45].

FIGURE 2

Differences in maternal‐fetal interface macrophage polarization in healthy pregnancy and PE. (1) Decidual macrophages are involved in uterine spiral artery remodeling. During normal pregnancy, uterine spiral arteries are remodeled into wide‐lumen spiral arteries due to trophoblast invasion and the secretion of vascular endothelial growth factor (VEGF) by M2 macrophages, providing sufficient oxygen and nutrients for subsequent embryonic development. (2) In PE, insufficient trophoblast invasion and a decreased proportion of M2 macrophages result in inadequate spiral artery remodeling, leading to narrow lumens, increased inflammatory substances at the maternal‐fetal interface, elevated oxidative stress, and trophoblast apoptosis.