Decidual macrophage-mediated ferroptosis in trophoblasts leads to recurrent spontaneous abortion

Abstract

Recurrent spontaneous abortion (RSA) poses a significant challenge to successful early pregnancy, and trophoblast cell ferroptosis is an important pathogenic mechanism of RSA. However, it remains unclear whether decidual macrophages, as key immune regulators at the maternal–fetal interface, participate in the regulation of ferroptosis in trophoblast cells. This study observed significant ferroptosis in the placental trophoblast cells of patients with RSA and aborted mice. Transcriptomic sequencing results revealed that decidual macrophages derived from patients with RSA significantly promoted trophoblast cell ferroptosis while simultaneously impairing trophoblast cell function. Mechanistically, silencing heme oxygenase 1 (HMOX1) in trophoblast cells effectively reversed ferroptosis and restored trophoblast cell function, which was inhibited by decidual macrophages derived from patients with RSA. Notably, decidual macrophages regulate trophoblast ferroptosis and function by secreting C-X-C motif chemokine ligand 2 (CXCL2). Furthermore, the nuclear factor kappa-B (NF-κB) pathway was significantly enriched in trophoblast cells co-cultured with decidual macrophages derived from patients with RSA. Further reversal experiments indicated that the CXCL2/NF-κB/HMOX1 signaling axis may be a crucial mechanism by which decidual macrophages regulate trophoblast cell ferroptosis and function in RSA. Our subsequent findings demonstrated that trophoblast cells co-cultured with RSA-derived decidual macrophages promoted pro-inflammatory polarization in macrophages. This effect was mediated by the interleukin-6 (IL-6) deficiency-inhibited janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. Finally, pharmacological analysis revealed Eriodictyol exhibits CXCL2-axis-associated protective effects in RSA. In conclusion, we observed that decidual macrophages in patients with RSA can induce ferroptosis in trophoblast cells, implying that targeting this mechanism may offer novel opportunities for reshaping maternal-fetal tolerance.

Keywords

CXCL2/NF-κB/HMOX1 axis / decidual macrophage / ferroptosis / recurrent spontaneous abortion / trophoblast cells

References

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