ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1629370
This article is part of the Research TopicCommunity Series in Unraveling the Molecular Mechanisms of Cytokine Signaling in Regulating Inflammatory Diseases: Volume ⅡView all 5 articles
Reciprocal activation between M1 macrophages and trophoblasts through CXCL9/STAT1/ZEB1/CCL2 axis promotes recurrent spontaneous abortion
Provisionally accepted
- Zhongnan Hospital, Wuhan University, Wuhan, China
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Abstract 1 Background 2 The crosstalk between macrophages and trophoblasts plays a crucial role in the 3 development and progression of recurrent spontaneous abortion (RSA). Although M1 4 macrophages (M1-Mφ) are known to accumulate in RSA decidual tissues, their direct 5 functional impact on trophoblasts remains poorly characterized. 6 Methods 7 We established an M1-Mφ-trophoblast coculture system to investigate this 8 interaction. CXCL9 expression was quantified in clinical samples and cell lines using 9 qPCR, ELISA, and immunofluorescence. The Mmigration and invasion capacities of 10 trophoblasts were evaluated through wound healing and Transwell assays. A series of 11 rescue experiments were conducted to uncover the underlying mechanism. Finally, an 12 in vivo animal model was carried out to validate the corresponding functions of the 13 CXCL9-related axis. 14 Results 15 Our results revealed that M1-Mφ inhibited the migration and invasion of trophoblasts 16 by releasing CXCL9. The expression of CXCL9 in decidual tissues was significantly 17 increased in RSA samples compared to healthy controls. Mechanistically, CXCL9 18 activated the CXCR3-dependent JAK/STAT1 signaling pathway. Activated STAT1 19 induced transcriptional upregulation of ZEB1 via IRF1, which in turn promoted the 20 release of CCL2 to enhance macrophage recruitment. In vivo, inhibition of CXCL9 21 reduced embryo resorption in LPS-induced abortion mice, attenuated macrophage 22 infiltration, and restored trophoblast migration and invasion. 23 Conclusion 24 Our work identifies a novel mechanism by which M1-Mφ regulate trophoblast 25 migration and invasion through the CXCL9/STAT1/IRF1/ZEB1 axis, which in turn 26 leads to the release of CCL2 that promotes macrophage infiltration in RSA, highlighting 27 a new form of crosstalk between macrophages and trophoblasts.
Keywords: Recurrent spontaneous abortion, M1-Mφ, Trophoblasts, CXCL9, migration and invasion, EMT
Received: 15 May 2025; Accepted: 21 Oct 2025.
Copyright: © 2025 Yan, Ding and Qiu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hiu Qiu, qiuhuiznyy@whu.edu.cn
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