{"title":"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","authors":"Qing Wang, Yining Cao, Songyi Ye, Maoyuan Ding, Wenliang Ge, Yuejin Liang, Jinling Chen","doi":"10.1371/journal.ppat.1012543","DOIUrl":null,"url":null,"abstract":"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 <jats:italic>Toxoplasma gondii</jats:italic> (<jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>) in the pathology of <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>-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 <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection remain elusive. In the present study, we found that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection downregulated Trem2 expression and that Trem2<jats:sup>-/-</jats:sup> mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2<jats:sup>-/-</jats:sup> pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> 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 <jats:italic>Tg</jats:italic>Ag 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 <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> antigens-treated BMDMs. Furthermore, compelling evidence from animal models and <jats:italic>in vitro</jats:italic> cell experiments suggests that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> 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 <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>-induced adverse pregnancy.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"20 1","pages":""},"PeriodicalIF":6.7000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages\",\"authors\":\"Qing Wang, Yining Cao, Songyi Ye, Maoyuan Ding, Wenliang Ge, Yuejin Liang, Jinling Chen\",\"doi\":\"10.1371/journal.ppat.1012543\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 <jats:italic>Toxoplasma gondii</jats:italic> (<jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>) in the pathology of <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>-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 <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection remain elusive. In the present study, we found that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection downregulated Trem2 expression and that Trem2<jats:sup>-/-</jats:sup> mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2<jats:sup>-/-</jats:sup> pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> 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 <jats:italic>Tg</jats:italic>Ag 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 <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> antigens-treated BMDMs. Furthermore, compelling evidence from animal models and <jats:italic>in vitro</jats:italic> cell experiments suggests that <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> 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 <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic> infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of <jats:italic>T</jats:italic>. <jats:italic>gondii</jats:italic>-induced adverse pregnancy.\",\"PeriodicalId\":20178,\"journal\":{\"name\":\"PLoS Pathogens\",\"volume\":\"20 1\",\"pages\":\"\"},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2024-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PLoS Pathogens\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1371/journal.ppat.1012543\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Immunology and Microbiology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS Pathogens","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1371/journal.ppat.1012543","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Immunology and Microbiology","Score":null,"Total":0}
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.
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.