The CCL2-CCR2 axis regulates increased monocyte-macrophage infiltration in unexplained recurrent miscarriage

Unexplained recurrent miscarriage (URM) is a complex reproductive disorder whose pathogenic immune factors remain unclear. The uterine decidual inflammatory microenvironment, characterized by increased pro-inflammatory macrophages and pro-inflammatory cytokines, may be associated with the pathogenesis of URM. This study aims to investigate the mechanisms underlying increased monocyte-macrophage infiltration in URM decidua. In URM decidua, specific monocyte-macrophage subtypes exhibited high expression of CCL2 or CCR2, as well as TNF and IL1B genes. Cell-cell communication analysis revealed that monocyte-macrophage subtypes are regulated by IFN-γ and CCL signaling. PD-1 + CD8+ T cells showed high expression of IFNG gene and were enriched in IFN-γ response gene sets. In vitro experiments confirmed increased expression of PD-1, IFN-γ, CCL2, and CCR2 in URM endometrium and decidua tissues. An increased proportion of macrophages and the presence of PD-1 + IFN-γ + T cells were observed in URM decidua. Macrophages secreted higher levels of CCL2 under IFN-γ stimulation. CCL2 promoted the migration of THP-1 cells, an effect that was inhibited by a CCR2 antagonist or prednisolone. This study reveals that the CCL2-CCR2 axis regulates increased monocyte-macrophage infiltration in URM decidua, and IFN-γ derived from PD-1 + T cells may drive enhanced CCL2 secretion. Prednisolone can inhibit IFN-γ-induced CCL2 secretion by macrophages and the chemotactic effect of CCL2 on THP-1 cells.