FOLR2+蜕膜巨噬细胞缺陷诱导的免疫激活损害自发性流产中的蜕膜化和血管生成

Abstract

BackgroundDecidual macrophages maintain immune tolerance and support decidualization at the maternal–fetal interface. However, the heterogeneity and functions of macrophage subsets in recurrent spontaneous abortion (RSA) remain unclear.MethodsWe integrated single-cell RNA sequencing of human endometrium and decidua with clinical validation. Functional assays using THP-1–derived macrophages and the co-culture with decidual stromal cells were performed to characterize macrophage subsets and investigate their roles in decidualization and RSA pathogenesis.ResultsA subset of FOLR2+ macrophages enriched in the decidua showed an M2-like immunoregulatory phenotype. In RSA decidua, FOLR2 expression and the proportion of FOLR2+ macrophages were markedly reduced, accompanied by increased inflammatory signaling and impaired angiogenic and adhesion interactions. Functional assays showed that FOLR2 overexpression enhanced immunoregulatory, tissue-resident, and pro-angiogenic properties, whereas FOLR2 silencing promoted inflammatory responses and impaired angiogenesis. Reciprocal crosstalk between DSCs and FOLR2+ macrophages established a positive feedback loop that promoted stromal decidualization and supported pregnancy maintenance.ConclusionsFOLR2+ macrophages represent an immunoregulatory subset at the maternal–fetal interface with tissue-resident and pro-angiogenic features. The loss of FOLR2+ macrophages in RSA may contribute to immune dysregulation and defective decidualization, providing new insights into the immune mechanisms underlying RSA pathogenesis.