Toxoplasma gondii-induced adverse pregnancy outcomes: insight into the inhibitory role of Trem2 on TLR4/TRAF6/JNK signaling pathway.

IF 3.5 2区医学 Q1 PARASITOLOGY

Parasites & Vectors Pub Date : 2025-10-06 DOI:10.1186/s13071-025-07000-w

Yining Cao, Feifei Fu, Fei Ju, Chenyu Wu, Tiankun Yao, Mei Yang, Baolan Sun, Jinling Chen

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Abstract

Background: Decidual macrophages (dMφs) are not only essential for maintaining normal pregnancy but also serve as crucial immune defenders against infections, including Toxoplasma gondii. Triggering receptor expressed on myeloid cells 2 (Trem2), as a critical immunoregulatory receptor on dMφs, can counteract inflammation and defend against pathogen infection. However, the mechanisms underlying the Trem2 downstream pathways during T. gondii infection-particularly their impact on adverse pregnancy outcomes (APOs)-remain elusive.

Methods: The interaction between Trem2 and Toll-like receptor 4 (TLR4) was initially predicted through molecular docking models and subsequently confirmed by co-immunoprecipitation, using both animal models and cellular systems to examine the impact of Trem2 knockout, overexpression, and TLR4-blocking antibody treatment on downstream signaling molecules as well as cytokine production.

Results: The interaction between Trem2 and TLR4 was validated. Trem2 downregulation during T. gondii infection coincided with increased TLR4, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), and c-Jun N-terminal kinase (JNK) activation, while Trem2 knockout further enhanced TLR4/TRAF6/JNK signaling in mice and macrophages. Conversely, Trem2 overexpression suppressed this signaling cascade and reversed T. gondii-induced activation. Treatment with a TLR4-blocking antibody inhibited TRAF6 and P-JNK activation in macrophages but did not affect Trem2 expression. Additionally, Trem2-deficient bone marrow-derived macrophages (BMDMs) exhibited elevated transcription of TNF-α and interferon-γ (IFN-γ) upon T. gondii antigen stimulation.

Conclusions: Trem2 deficiency in pregnant mice promotes the TLR4/TRAF6/JNK signaling cascade following T. gondii infection. This study demonstrates that Trem2 acts as a pregnancy-specific inhibitor of TLR4/TRAF6/JNK signaling, providing novel mechanistic insights into T. gondii-induced APOs.

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刚地弓形虫诱导的不良妊娠结局：Trem2对TLR4/TRAF6/JNK信号通路的抑制作用

背景：蜕膜巨噬细胞（dMφs）不仅对维持正常妊娠至关重要，而且是抵抗包括弓形虫在内的感染的重要免疫防御者。髓样细胞上表达的触发受体2 （Trem2）是dMφs上重要的免疫调节受体，具有抵抗炎症和防御病原体感染的作用。然而，弓形虫感染期间Trem2下游通路的机制，特别是它们对不良妊娠结局（APOs）的影响，仍然是难以捉摸的。方法：通过分子对接模型初步预测Trem2和toll样受体4 （TLR4）之间的相互作用，随后通过共免疫沉淀证实，使用动物模型和细胞系统检测Trem2敲除、过表达和TLR4阻断抗体处理对下游信号分子和细胞因子产生的影响。结果：证实了Trem2与TLR4的相互作用。弓形虫感染期间Trem2的下调与TLR4、肿瘤坏死因子（TNF）受体相关因子6 （TRAF6）和c-Jun n -末端激酶（JNK）激活的增加相一致，而敲除Trem2进一步增强了小鼠和巨噬细胞中TLR4/TRAF6/JNK信号传导。相反，Trem2过表达抑制了这一信号级联，逆转了弓形虫诱导的激活。tlr4阻断抗体抑制巨噬细胞中TRAF6和P-JNK的激活，但不影响Trem2的表达。此外，trem2缺陷的骨髓源性巨噬细胞（bmdm）在弓形虫抗原刺激下表现出TNF-α和干扰素-γ (IFN-γ)的转录升高。结论：孕鼠tre2缺乏可促进弓形虫感染后TLR4/TRAF6/JNK信号级联反应。本研究表明，Trem2作为TLR4/TRAF6/JNK信号的妊娠特异性抑制剂，为弓形虫诱导的APOs提供了新的机制见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Parasites & Vectors 医学-寄生虫学

CiteScore

6.30

自引率

9.40%

发文量

433

审稿时长

1.4 months

期刊介绍： Parasites & Vectors is an open access, peer-reviewed online journal dealing with the biology of parasites, parasitic diseases, intermediate hosts, vectors and vector-borne pathogens. Manuscripts published in this journal will be available to all worldwide, with no barriers to access, immediately following acceptance. However, authors retain the copyright of their material and may use it, or distribute it, as they wish. Manuscripts on all aspects of the basic and applied biology of parasites, intermediate hosts, vectors and vector-borne pathogens will be considered. In addition to the traditional and well-established areas of science in these fields, we also aim to provide a vehicle for publication of the rapidly developing resources and technology in parasite, intermediate host and vector genomics and their impacts on biological research. We are able to publish large datasets and extensive results, frequently associated with genomic and post-genomic technologies, which are not readily accommodated in traditional journals. Manuscripts addressing broader issues, for example economics, social sciences and global climate change in relation to parasites, vectors and disease control, are also welcomed.