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  3. Galectin-9 in human trophoblast cells: Implications for maternal-fetal immune balance and pregnancy complications

Galectin-9 in human trophoblast cells: Implications for maternal-fetal immune balance and pregnancy complications

  • Life Sci. 2026 Mar 1:388:124173. doi: 10.1016/j.lfs.2025.124173.
Xuqing He 1,  Penghao Li 1,  Jingliang Xu 2,  Jingxian Zhang 3,  Yungang Liu 4,  Ju Huang 5,  Xinrui Chi 2,  Qiaoxin Zhang 5,  Yanrong Chen 5,  Jin Huang 6,  Hui Wang 6,  Zhengping Zhuang 7,  Jiang Gu 8
Affiliations

Affiliations

  • 1 Jinxin Reproductive and Genetic Research Institute, Xinan Gynecology Hospital, Chengdu, China; Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China.
  • 2 Jinxin Reproductive and Genetic Research Institute, Xinan Gynecology Hospital, Chengdu, China.
  • 3 Shantou University Medical College, Shantou, China.
  • 4 Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, Guangzhou, 510515, China.
  • 5 First Affiliated Hospital of Shantou University, Shantou, China.
  • 6 Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China.
  • 7 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, United States of America.
  • 8 Jinxin Reproductive and Genetic Research Institute, Xinan Gynecology Hospital, Chengdu, China; Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China. Electronic address: [email protected].
PMID: 41544754 DOI: 10.1016/j.lfs.2025.124173
Abstract

Introduction: Galectin-9 (Gal-9) is a multifunctional protein belonging to the β-galactoside-binding lectin family playing crucial roles in immune regulation of tumor and pregnancy. However, its roles in placental pathophysiology such as preeclampsia have not been well understood. In this study the involvement of Gal-9 in trophoblast functioning and sustained immune balance were explored.

Methods: Immortalized human trophoblast cells (HTR-8/SVneo) were subjected to chemical hypoxia (induced by CoCl2) and oxidative stress (induced by HMGB1), then treated with HIF-1α knockdown or specific inhibitors. Subsequently, Gal-9 and IgG4 (another newly established immune regulator of pregnancy) levels were analyzed with immunofluorescence assay and Western blotting, and in human placental tissues with immunohistochemistry; moreover, the invasiveness of HTR-8/SVneo cells co-cultured with peripheral blood mononuclear cells (PBMCs) was evaluated with transwell assay, and IgG4 determined with ELISA and Western blotting.

Results: Both chemical hypoxia and oxidative stress induced Gal-9 expression in HTR-8/SVneo cells, which were initiated by the elevation of HIF-1 and Apoptosis signal-regulating kinase 1 (ASK1), respectively. Interestingly, IgG4 secretion from PBMCs co-cultured with HTR-8/SVneo was dependent on the duration of hypoxia: it was enhanced up to day 5 but inhibited by day 7, with persistent elevation of Gal-9 but Apoptosis of PBMCs under prolonged hypoxia.

Conclusion: Hypoxia and oxidative stress upregulate trophoblast Gal-9 through distinct mechanisms. Hypoxia duration affects IgG4 production in co-cultures-enhanced short-term but suppressed long-term-implying pathological placental hypoxia may increase Gal-9, reduce IgG4, and disrupt maternal-fetal immune balance. This newly discovered regulatory pathway of Gal-9 in the placenta during pregnancy may contribute to the pathogenesis of pregnancy-associated diseases including PE.

Keywords

Galectin-9 regulation; Hypoxia-induced pathways; IgG4 modulation; Maternal-fetal immune tolerance; Trophoblast-PBMC interactions.

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