A higher ratio of M1/M2 macrophages and an elevated chemerin level are both related to increased risk of preeclampsia. However, the crosstalk between these two events and their collective contribution to preeclampsia are not well understood. In this study, we assessed the impacts of chemerin chemokine-like receptor 1 (CMKLR1)/p-Akt/CEBPα axis in regulating macrophage polarization and mediating the pathogenic effects of chemerin on preeclampsia. We showed that chemerin, in a dose- and time-dependent manner, stimulated M1 macrophage polarization, inhibited macrophage-induced trophoblast invasion and migration, and suppressed macrophage-mediated angiogenesis. All these chemerin-induced phenotypes are essentially mediated by sequentially CMKLR1, Akt activation, and CEBPα. Mechanistically, CEBPα acted as a transcriptional activator for both IRF8 and chemerin. In vivo, chemerin aggravated preeclampsia, while α-NETA, an inhibitor for CMKLR1, significantly suppressed M1 macrophage polarization and alleviated preeclampsia. In summary, chemerin, by activating CMKLR1/Akt/CEBPα axis, forms a positive feedback loop, promotes M1 macrophage polarization, suppresses trophoblast migration/invasion and angiogenesis, and contributes to preeclampsia. Therefore, targeting chemerin signaling may benefit the prevention and/or treatment of preeclampsia.

Graphical abstract

中文翻译：

---

Chemerin通过激活CMKLR1/p-Akt/CEBPɑ轴和诱导M1巨噬细胞极化促进子痫前期的发病机制

M1/M2 巨噬细胞比例较高和凯莫瑞水平升高均与先兆子痫风险增加有关。然而，这两个事件之间的串扰及其对先兆子痫的集体贡献尚不清楚。在这项研究中，我们评估了凯莫瑞趋化因子样受体 1 (CMKLR1)/p-Akt/CEBPα 轴在调节巨噬细胞极化和介导凯莫瑞对先兆子痫的致病作用中的影响。我们发现凯莫瑞以剂量和时间依赖性方式刺激 M1 巨噬细胞极化，抑制巨噬细胞诱导的滋养层侵袭和迁移，并抑制巨噬细胞介导的血管生成。所有这些凯莫瑞诱导的表型基本上由 CMKLR1、Akt 激活和 CEBPα 依次介导。机械地，CEBPα 作为 IRF8 和凯莫瑞的转录激活剂。在体内，凯莫瑞加重先兆子痫，而 CMKLR1 抑制剂 α-NETA 显着抑制 M1 巨噬细胞极化并减轻先兆子痫。综上所述，凯莫瑞通过激活CMKLR1/Akt/CEBPα轴形成正反馈回路，促进M1巨噬细胞极化，抑制滋养细胞迁移/侵袭和血管生成，促进子痫前期。因此，靶向凯莫瑞信号可能有利于预防和/或治疗先兆子痫。抑制滋养层迁移/侵袭和血管生成，并导致先兆子痫。因此，靶向凯莫瑞信号可能有利于预防和/或治疗先兆子痫。抑制滋养层迁移/侵袭和血管生成，并导致先兆子痫。因此，靶向凯莫瑞信号可能有利于预防和/或治疗先兆子痫。

图形概要