Macrophage clock of pregnancy: circadian and metabolic control of decidual macrophage.

Abstract

The temporal regulation of immune responses during pregnancy is crucial for successful gestation. Yet, the specific mechanisms controlling macrophage function across gestational stages remain poorly understood. Here, we introduce the concept of the "macrophage clock of pregnancy", describing how molecular clock and cellular metabolism coordinate macrophage function across gestational stages. The molecular mechanisms underlying circadian control of macrophage function are examined, as well as hormones secreted by the pineal gland and their relevance to pregnancy-related processes. These pathways orchestrate key macrophage functions in pregnancy: modifying the uterine epithelium during implantation, supporting spiral artery remodeling, maintaining fetal tolerance, and initiating labor. Recent evidence shows that environmental factors such as shift work and extension of artificial light exposure can disturb macrophage function. The temporal regulation of macrophages also depends on metabolic signals, with distinct patterns of glycolysis, oxidative phosphorylation, and fatty acid metabolism corresponding to different gestational phases. Disruption of these temporal and metabolic signals - whether through circadian misalignment or metabolic dysfunction - correlates with pregnancy complications including recurrent pregnancy loss, preeclampsia, and preterm birth. We propose that monitoring macrophage temporal dynamics could provide early indicators of pregnancy complications, while targeting clock-controlled pathways may offer new therapeutic strategies. Understanding the temporal aspects of macrophage function opens new approaches for treating pregnancy disorders through precise immunological timing.