Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages

Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of Toxoplasma gondii (T. gondii) in the pathology of T. gondii-induced adverse pregnancy. Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in T. gondii infection remain elusive. In the present study, we found that T. gondii infection downregulated Trem2 expression and that Trem2-/- mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that T. gondii infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2-/- pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by T. gondii antigens through macrophages as an "intermediate bridge", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in T. gondii antigens-treated BMDMs. Furthermore, compelling evidence from animal models and in vitro cell experiments suggests that T. gondii inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to T. gondii infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of T. gondii-induced adverse pregnancy.定居于母胎界面的蜕膜巨噬细胞（decidual macrophages）已被证实为维持正常妊娠的关键调控因子；而在弓形虫（Toxoplasma gondii, T. gondii）诱导的不良妊娠病理进程中，这类细胞同时也是弓形虫感染的核心靶细胞。髓系细胞触发受体2（Trem2）作为巨噬细胞表面的功能性受体，可识别并结合多种病原体。然而，Trem2在弓形虫感染过程中的具体作用与潜在分子机制仍未明确。本研究发现，弓形虫感染会下调Trem2的表达；且与野生型小鼠相比，Trem2基因敲除（Trem2-/-）小鼠的不良妊娠结局更为严重。本研究同时证实，弓形虫感染会导致蜕膜巨噬细胞数量增多；而在Trem2-/-妊娠小鼠模型中，这类细胞的数量较野生型对照小鼠显著降低。本研究进一步揭示，弓形虫抗原可通过巨噬细胞作为“中间桥梁”，抑制滋养层细胞的增殖、迁移与侵袭功能；而Trem2激动剂热休克蛋白60（HSP60）可逆转这一抑制效应。与此同时，在骨髓源性巨噬细胞（bone marrow-derived macrophages, BMDMs）中敲除Trem2会增强弓形虫抗原对滋养层细胞迁移与侵袭的抑制作用；经弓形虫抗原处理的BMDMs中，促炎因子白细胞介素1β（IL-1β）、白细胞介素6（IL-6）及肿瘤坏死因子α（TNF-α）水平升高，而趋化因子CXC配体1（CXCL1）的表达水平显著降低。此外，动物模型与体外细胞实验的有力证据表明，弓形虫可抑制Trem2-脾酪氨酸激酶（Syk）-磷脂酰肌醇3-激酶（PI3K）信号通路，进而导致蜕膜巨噬细胞功能受损。综上，本研究结果证实，Trem2信号通路是蜕膜巨噬细胞应对弓形虫感染的核心通路，提示Trem2是蜕膜巨噬细胞的关键感受受体，同时也可作为弓形虫诱导不良妊娠病理过程中的潜在治疗靶点。