Chemerin promotes the pathogenesis of preeclampsia by activating CMKLR1/p-Akt/CEBPɑ axis and inducing M1 macrophage polarization

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 chemoki...

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Published in:Cell biology and toxicology 2022-08, Vol.38 (4), p.611-628
Main Authors: Ji, Zhi-Song, Jiang, Hua, Xie, Yue, Wei, Qi-Peng, Yin, Xiao-Fang, Ye, Jin-Hai, Quan, Xiao-Zhen, Lan, Yan-Li, Zhao, Meng, Tian, Xiao-Long, Zhang, Ya-Jun, Yang, Xue-Zhou
Format: Article
Language:English
Subjects:
AKT protein
Angiogenesis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Chemokines
Crosstalk
Feedback loops
Leukocyte migration
Life Sciences
Macrophages
Original Article
Pathogenesis
Pharmacology/Toxicology
Phenotypes
Polarization
Positive feedback
Pre-eclampsia
Preeclampsia
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Summary: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
ISSN:0742-2091
1573-6822
DOI:10.1007/s10565-021-09636-7