Trem2-MICAL1-P-ERK Axis in Macrophages Confers Protection Against Toxoplasma gondii-Induced Adverse Pregnancy Outcomes

Toxoplasma gondii (T. gondii) infection during pregnancy can cause severe placental damage and fetal impairment. 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.