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Research Article: Immune activation induced by FOLR2 + decidual macrophage deficiency impairs decidualization and angiogenesis in spontaneous abortion

Date Published: 2026-06-23

Abstract:
Decidual 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. We 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. A 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. FOLR2 + 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.

Introduction:
Decidual 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.

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