Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, Wayne State University, Detroit, Michigan, USA.
FASEB J. 2022 Jan;36(1):e22073. doi: 10.1096/fj.202101306R.
Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) are important immune checkpoint receptors that prevent an overreacted maternal immune response to fetal antigens during pregnancy. Disruption of complex immune regulation mechanisms is associated with adverse pregnancy outcomes, including preeclampsia (PE). Our recent study showed that the Tim-3 pathway was involved in the regulation of decidual macrophage polarization. Decidual macrophages polarized to the M1 phenotype may impair uterine vessel remodeling during placentation, accounting for the occurrence of PE. Co-blockade of the PD-1/Tim-3 pathway was shown to successfully control tumor growth in preclinical cancer models. However, the effects of activating both PD-1 and Tim-3 pathways as a combined intervention strategy in PE are never reported. Herein, we observed the skew of decidual macrophage polarization toward the M1 phenotype in patients with PE and lipopolysaccharide (LPS)-induced PE-like rat model. Moreover, we found that the activation of PD-1/Tim-3 pathway by using PD-L1 and Gal-9 fusion proteins could alleviate the manifestation of the LPS-induced PE-like rats and protect their offspring. Compared with the single intervention, the combination of PD-L1and Gal-9 fusion proteins exhibited obvious advantages in the relief of PE-like symptoms, trophoblast invasion, and fetal vascular development, indicating a synergistic effect of the activated PD-1/Tim-3 pathway. The in vitro study also revealed that the combined intervention using PD-L1 and Gal-9 fusion proteins inhibited the LPS-induced M1 macrophage polarization via the synergic activation of the ERK/GSK3β/β-catenin signaling pathway. Together, our findings provide the first evidence that simultaneous activation of PD-1/Tim-3 signaling pathways may have an optimal protective effect and serve as a new potential target for PE intervention.
程序性细胞死亡受体-1（PD-1）和 T 细胞免疫球蛋白黏蛋白-3（Tim-3）是重要的免疫检查点受体，可防止妊娠期间母体免疫系统对胎儿抗原过度反应。复杂免疫调节机制的破坏与不良妊娠结局有关，包括子痫前期（PE）。我们最近的研究表明，Tim-3 途径参与了蜕膜巨噬细胞极化的调节。向 M1 表型极化的蜕膜巨噬细胞可能会损害胎盘形成过程中的子宫血管重塑，导致 PE 的发生。在临床前癌症模型中，共阻断 PD-1/Tim-3 通路已被证明可成功控制肿瘤生长。然而，激活 PD-1 和 Tim-3 通路作为联合干预策略在 PE 中的作用从未有报道。在此，我们观察到 PE 患者和脂多糖（LPS）诱导的 PE 样大鼠模型中蜕膜巨噬细胞向 M1 表型的极化偏斜。此外，我们发现使用 PD-L1 和 Gal-9 融合蛋白激活 PD-1/Tim-3 通路可以减轻 LPS 诱导的 PE 样大鼠的表现并保护其后代。与单一干预相比，PD-L1 和 Gal-9 融合蛋白的联合干预在缓解 PE 样症状、滋养细胞侵袭和胎儿血管发育方面表现出明显优势，表明激活的 PD-1/Tim-3 通路具有协同作用。体外研究还表明，PD-L1 和 Gal-9 融合蛋白的联合干预通过协同激活 ERK/GSK3β/β-catenin 信号通路抑制 LPS 诱导的 M1 巨噬细胞极化。总之，我们的研究结果首次提供了证据，表明同时激活 PD-1/Tim-3 信号通路可能具有最佳的保护作用，并可作为 PE 干预的新潜在靶点。
