Trem2/Syk/PI3K轴通过调节蜕膜巨噬细胞,帮助宿主抵御弓形虫诱发的不良妊娠结局

IF 6.7 1区 医学 Q1 Immunology and Microbiology PLoS Pathogens Pub Date : 2024-09-09 DOI:10.1371/journal.ppat.1012543
Qing Wang, Yining Cao, Songyi Ye, Maoyuan Ding, Wenliang Ge, Yuejin Liang, Jinling Chen
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引用次数: 0

摘要

驻留在母胎界面的蜕膜巨噬细胞被认为是维持正常妊娠的关键因素,但它们也是弓形虫(T. gondii)在T. gondii引起的不良妊娠病理学中的关键靶细胞。Trem2 作为巨噬细胞表面的功能性受体,可识别并结合各种病原体。Trem2在淋病双球菌感染中的作用及其内在机制仍未确定。在本研究中,我们发现淋球菌感染会下调Trem2的表达,Trem2-/-小鼠比野生型小鼠表现出更严重的不良妊娠结局。我们还证实,淋球菌感染导致蜕膜巨噬细胞增加,与野生型对照组相比,Trem2-/-妊娠小鼠模型中的巨噬细胞显著减少。我们进一步描述了淋球菌抗原通过巨噬细胞这一 "中间桥梁 "对滋养层细胞增殖、迁移和侵袭功能的抑制作用,而这种抑制作用可被Trem2激动剂HSP60所挽救。同时,骨髓源性巨噬细胞(BMDMs)缺乏Trem2会增强TgAg对滋养层细胞迁移和侵袭的抑制作用,同时T.gondii抗原处理的BMDMs中的促炎因子(IL-1β、IL-6和TNF-α)较高,而趋化因子(CXCL1)较低。此外,来自动物模型和体外细胞实验的有力证据表明,淋球菌抑制了Trem2-Syk-PI3K信号通路,导致蜕膜巨噬细胞功能受损。因此,我们的研究结果突显了Trem2信号传导是蜕膜巨噬细胞对淋病双球菌感染做出反应的重要途径,这表明Trem2是蜕膜巨噬细胞的一个关键传感器,也是淋病双球菌诱导的不良妊娠病理学的潜在治疗靶点。
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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.
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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