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Although triggering the receptor expressed on myeloid cells 2 (Trem2) confers protection against T. gondii infection, the precise molecular mechanisms underlying this immunoregulatory role remain incompletely understood. Using a mouse model, this study identifies a novel Trem2-MICAL1-P-ERK axis in macrophages that protects against T. gondii-induced adverse pregnancy outcomes (APO). RNA-seq of Trem2-overexpressing macrophages revealed significant upregulation of 1857 genes, with MICAL1 among the most markedly altered, highlighting its potential role in Trem2-mediated signaling. Mechanistically, correlation analysis, molecular docking, fluorescence co-localization, and immunoprecipitation assays demonstrate that Trem2 directly interacts with MICAL1, which modulates downstream phosphorylated ERK (P-ERK) signaling. In a T. gondii-infected murine pregnancy model, genetic ablation of Trem2 exacerbated pathogen-induced suppression of MICAL1 and P-ERK, whereas macrophage-specific overexpression of Trem2-DAP12 restored this signaling axis. Conversely, MICAL1 overexpression rescued P-ERK activation but failed to regulate Trem2 expression. Further studies in bone marrow-derived macrophages (BMDMs) revealed that Trem2 deficiency potentiated the inhibitory effects of soluble T. gondii antigens (TgAg) on MICAL1 and P-ERK. These findings elucidate how T. gondii disrupts placental immunity through targeted suppression of Trem2-mediated signaling and establish the Trem2-MICAL1-P-ERK cascade as a core regulatory pathway in immune homeostasis during pregnancy.<\/jats:p>","DOI":"10.3390\/pathogens14111105","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:23:59Z","timestamp":1761873839000},"page":"1105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Trem2-MICAL1-P-ERK Axis in Macrophages Confers Protection Against Toxoplasma gondii-Induced Adverse Pregnancy Outcomes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4195-6861","authenticated-orcid":false,"given":"Xiaoyu","family":"Geng","sequence":"first","affiliation":[{"name":"Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haochen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinling","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Reim\u00e3o, J.Q., Evangelista, F.F., Alves, S.O., Torres, T., Lobo, J.d.E.S., Perroni, K.T.R., and Mariante, R.M. 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