Hofbauer Macrophages and FXIIIA1 Expression: Immunoregulatory, Angiogenic, and Clinical Implications in Pregnancy

Hofbauer macrophages (HCs) are central regulators of placental biology, acting as key mediators of immune surveillance, tissue remodeling, angiogenesis, and homeostasis at the maternal–fetal interface. Their immunoregulatory nature shaped by both foetal and maternal cues, supports healthy foetal development and maintains a tolerogenic microenvironment. Factor XIII A1 (FXIIIA1), a transglutaminase involved in extracellular matrix cross-linking and immune modulation, has emerged as a critical determinant of HC phenotype and function. Increasing evidence suggests that FXIIIA1 expression enhances placental resilience, supports vascular development, and shapes HC responses to infectious or inflammatory stressors. Understanding the molecular pathways linking HC biology and FXIIIA1 activity will deepen our insight into normal placental development and the pathogenesis of pregnancy complications. Moreover, delineating how maternal infections, metabolic conditions, and drug exposures influence HC behavior may open new therapeutic avenues for improving pregnancy outcomes. • Hofbauer cell–specific FXIIIA1 links placental macrophage function to angiogenesis, immune regulation, and coagulation, positioning macrophage-driven pathways as central determinants of placental resilience and adverse outcomes such as preterm birth, foetal growth restriction and preeclampsia.