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. Author summary: T. gondii is a critically important intracellular protozoan that is a major cause of adverse pregnancy outcomes in humans and livestock. The pathology of adverse pregnancy induced by T. gondii involves the dysfunction of decidual macrophages. Trem2, a functional immune receptor on the surface of decidual macrophages, governs its survival and phagocytosis. Here, we sought to elucidate whether Trem2 signaling is involved in the pathology of T. gondii-induced adverse pregnancy. We found that T. gondii infection led to the downregulation of Trem2 expression in macrophages, both in vivo and in vitro. Trem2-/- mice exhibit more severe adverse pregnancy outcomes after T. gondii infection. 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. In parallel, Trem2 deficiency in BMDMs heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells. Our work uncovers an important factor involved in the pathological mechanism of T. gondii-induced adverse pregnancy, and research on Trem2 may provide new preventive and therapeutic targets for toxoplasmosis. [ABSTRACT FROM AUTHOR]