A Galectin-9-Driven CD11chigh Decidual Macrophage Subset Suppresses Uterine Vascular Remodeling in Preeclampsia

Yanhong Li; Yifei Sang; Yunjian Chang; Chunfang Xu; Yikong Lin; Yao Zhang; Philip C N Chiu; William S B Yeung; Haisheng Zhou; Ningzheng Dong; Ling Xu; Jiajia Chen; Weijie Zhao; Lu Liu; Di Yu; Xingxing Zang; Jiangfeng Ye; Jinying Yang; Qingyu Wu; Dajin Li; Ligang Wu; Meirong Du

doi:10.1161/CIRCULATIONAHA.123.064391

A Galectin-9-Driven CD11c^high Decidual Macrophage Subset Suppresses Uterine Vascular Remodeling in Preeclampsia

Circulation. 2024 Feb 5. doi: 10.1161/CIRCULATIONAHA.123.064391. Online ahead of print.

Authors

Yanhong Li^#^{1

2

3}, Yifei Sang^#¹, Yunjian Chang^#⁴, Chunfang Xu^#¹, Yikong Lin^{1

2}, Yao Zhang⁴, Philip C N Chiu^{5

6}, William S B Yeung⁶, Haisheng Zhou^{4

5}, Ningzheng Dong⁷, Ling Xu¹, Jiajia Chen¹, Weijie Zhao^{1

2}, Lu Liu¹, Di Yu^{8

9}, Xingxing Zang¹⁰, Jiangfeng Ye¹¹, Jinying Yang², Qingyu Wu⁷, Dajin Li¹, Ligang Wu⁴, Meirong Du^{1

2

3

12}

Affiliations

¹ Laboratory of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University Shanghai Medical College, China (Y. Li, Y.S., C.X., Y. Lin, L.X., J.C., W.Z., L.L., D.L., M.D.).
² Department of Obstetrics, Longgang District Maternity and Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Clinical Institute of Shantou University Medical College), Shenzhen, Guangdong, China (Y. Li, Y. Lin, W.Z., J. Yang, M.D.).
³ Department of Obstetrics and Gynecology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University Shanghai, China (Y. Li, M.D.).
⁴ State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China (Y.C., Y.Z., H.Z., L.W.).
⁵ Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, China (P.C.N.C., W.S.B.Y.).
⁶ The University of Hong Kong Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China (P.C.N.C., W.S.B.Y.).
⁷ Cyrus Tang Hematology Center, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China (N.D., Q.W.).
⁸ The University of Queensland Diamantina Institute (D.Y.), Faculty of Medicine, The University of Queensland, Brisbane, Australia.
⁹ Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre (D.Y.), Faculty of Medicine, The University of Queensland, Brisbane, Australia.
¹⁰ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY (X.Z.).
¹¹ Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore City, Singapore (J. Ye).
¹² State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau SAR, China (M.D.).

^# Contributed equally.

PMID: 38314577
DOI: 10.1161/CIRCULATIONAHA.123.064391

Abstract

Background: Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral arteries are implicated in preeclampsia, but the mechanistic link remains unclear.

Methods: Single-cell RNA sequencing and spatial transcriptomics were used to identify immune cell subsets associated with preeclampsia. Cell-based studies and animal models including conditional knockout mice and a new preeclampsia mouse model induced by recombinant mouse galectin-9 were applied to validate the pathogenic role of a CD11c^high subpopulation of decidual macrophages (dMφ) and to determine its underlying regulatory mechanisms in preeclampsia. A retrospective preeclampsia cohort study was performed to determine the value of circulating galectin-9 in predicting preeclampsia.

Results: We discovered a distinct CD11c^high dMφ subset that inhibits spiral artery remodeling in preeclampsia. The proinflammatory CD11c^high dMφ exhibits perivascular enrichment in the decidua from patients with preeclampsia. We also showed that trophoblast-derived galectin-9 activates CD11c^high dMφ by means of CD44 binding to suppress spiral artery remodeling. In 3 independent preeclampsia mouse models, placental and plasma galectin-9 levels were elevated. Galectin-9 administration in mice induces preeclampsia-like phenotypes with increased CD11c^high dMφ and defective spiral arteries, whereas galectin-9 blockade or macrophage-specific CD44 deletion prevents such phenotypes. In pregnant women, increased circulating galectin-9 levels in the first trimester and at 16 to 20 gestational weeks can predict subsequent preeclampsia onset.

Conclusions: These findings highlight a key role of a distinct perivascular inflammatory CD11c^high dMφ subpopulation in the pathogenesis of preeclampsia. CD11c^high dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.

Keywords: galectins; gene expression profiling; macrophages; preeclampsia; pregnancy; sequence analysis, RNA; trophoblasts.