Department of Obstetrics and Gynecology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China.
Reproduction. 2021 Jan;161(1):1-10. doi: 10.1530/REP-19-0543.
To obtain a successful pregnancy, trophoblasts must provide a physical barrier, suppress maternal reactivity, produce immunosuppressive hormones locally, and enhance the production of blocking factors that are able to bind to several antigenic sites. Inadequate placental perfusion has been closely associated with several pregnancy-associated diseases. Galectin-9 (Gal-9) has a wide variety of regulatory functions in innate and adaptive immunity during infection, tumor growth, and organ transplantation. We utilized immortalized human first-trimester extravillous trophoblast cells (HTR8/SVneo) for our functional study and examined the effects of Gal-9 on apoptosis, cytokine production and angiogenesis of HTR8/SVneo cells. Gal-9 inhibited the apoptosis and IFN-γ and IL-17A production, promoted IL-4 production, and coordinated the crosstalk between HTR8/SVneo cells and human umbilical vein endothelial cells via its interaction with Tim-3. Blockade of JNK signaling inhibited Gal-9 activities in HTR8/SVneo cells. In addition, we detected a correlation between low levels of Gal-9 and spontaneous abortion. So Gal-9 could inhibit the apoptosis and proinflammatory cytokine expression, and promote the angiogenesis and IL-4 production in HTR8/SVneo cells via Tim-3 in a JNK dependent manner to help the maintenance of normal pregnancy. These findings possibly identify Gal-9 as a key regulator of trophoblast cells and suggest its potential as a biomarker and target for the treatment of recurrent pregnancy loss.
为了获得成功的妊娠，滋养层必须提供物理屏障，抑制母体反应性，局部产生免疫抑制激素，并增强能够结合多个抗原位点的阻断因子的产生。胎盘灌注不足与多种与妊娠相关的疾病密切相关。半乳糖凝集素-9（Gal-9）在感染、肿瘤生长和器官移植过程中的固有和适应性免疫中具有广泛的调节功能。我们利用永生化的人早孕绒毛外滋养层细胞（HTR8/SVneo）进行功能研究，并研究了 Gal-9 对 HTR8/SVneo 细胞凋亡、细胞因子产生和血管生成的影响。Gal-9 通过与 Tim-3 相互作用，抑制 HTR8/SVneo 细胞的凋亡和 IFN-γ和 IL-17A 的产生，促进 IL-4 的产生，并协调 HTR8/SVneo 细胞与脐静脉内皮细胞之间的串扰。JNK 信号通路的阻断抑制了 HTR8/SVneo 细胞中 Gal-9 的活性。此外，我们检测到 Gal-9 水平低与自然流产之间存在相关性。因此，Gal-9 可以通过 JNK 依赖性方式通过 Tim-3 抑制 HTR8/SVneo 细胞的凋亡和促炎细胞因子表达，并促进血管生成和 IL-4 的产生，有助于维持正常妊娠。这些发现可能将 Gal-9 鉴定为滋养层细胞的关键调节剂，并提示其作为复发性妊娠丢失的治疗靶点和生物标志物的潜力。
