Trem2–PLCγ2–Ca2+ signaling axis in macrophages: a protective mechanism disrupted by Toxoplasma gondii infection at the maternal–fetal interface

Toxoplasma gondii infection during pregnancy is associated with placental injury and adverse pregnancy outcomes, in which immune imbalance at the maternal–fetal interface plays an important role. Macrophages are essential myeloid cells that contribute to local immune homeostasis and tissue protection during pregnancy. Trem2 has been implicated in the regulation of macrophage function under inflammatory or stress conditions; however, its role and the underlying mechanism in T. gondii -associated pregnancy complications remain incompletely defined. Molecular docking and endogenous co-immunoprecipitation were performed to investigate the association between Trem2 and PLCγ2. A pregnant mouse model of T. gondii infection was established using wild-type and Trem2 −/− mice to assess pregnancy outcomes, placental pathology, and alterations in Trem2, PLCγ2, and intracellular Ca 2+ signaling. In parallel, RAW264.7 cells and primary bone marrow-derived macrophages were stimulated with T. gondii antigens in vitro to further evaluate changes in the Trem2–PLCγ2–Ca 2+ signaling axis. Trem2 was found to associate with PLCγ2, and this association was weakened following T. gondii -related stimulation. Mutation of key residues within the predicted binding interface markedly impaired Trem2–PLCγ2 association. In vivo, T. gondii infection led to fetal growth restriction and placental injury, accompanied by reduced Trem2 and PLCγ2 expression and attenuated Ca 2+ signaling in placental tissues. These pathological and signaling alterations were more evident in Trem2 −/− mice. Consistently, T. gondii antigens suppressed the Trem2–PLCγ2–Ca 2+ axis in RAW264.7 cells and primary bone marrow-derived macrophages, with a stronger inhibitory effect observed under Trem2-deficient conditions. These findings suggest that T. gondii infection disrupts a Trem2-dependent protective signaling program in macrophages by reducing Trem2 expression, weakening Trem2–PLCγ2 coupling, and impairing downstream Ca 2+ signaling. The Trem2–PLCγ2–Ca 2+ axis may therefore represent an important regulatory pathway involved in maternal–fetal immune homeostasis and placental protection during T. gondii -associated adverse pregnancy.