Trem2-MICAL1-P-ERK axis in macrophages confers protection against Toxoplasma gondii-induced adverse pregnancy outcomes
Description
Toxoplasma gondii (T. gondii) infection during pregnancy can cause severe placental damage and fetal impairment. Although triggering receptor expressed on myeloid cells 2 (Trem2) has been implicated in conferring protection against T. gondii infection, the precise molecular mechanisms underlying this immunoregulatory role remain incompletely understood. This study identifies a novel Trem2-MICAL1-P-ERK axis in macrophages that protects against T. gondii-induced adverse pregnancy outcomes (APO). RNA-seq analysis 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 both 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 mechanistic studies in bone marrow-derived macrophages revealed that Trem2 deficiency potentiated the inhibitory effects of T. gondii antigens on MICAL1 and P-ERK. Together, these findings elucidate T. gondii disrupts placental immunity through targeted suppression of Trem2-mediated signaling and establishes the Trem2-MICAL1-P-ERK cascade as a core regulatory pathway in immune homeostasis during pregnancy.