Trem2 prevents adverse pregnancy outcomes induced by Toxoplasma gondii by promoting PPARγ-mediated P-STAT6 signaling
Description
Decidual macrophages (DMs), required for the maintenance of a successful pregnancy, are vital target cells for Toxoplasma gondii (T. gondii) during adverse pregnancy induced by T. gondii. Trem2 is a functional immune receptor on the surface of DMs, governing cell survival and phagocytosis. The role of Trem2 and its downstream signaling pathways in T. gondii-induced adverse pregnancy outcomes remains unclear. Here, we demonstrated a significant decrease in Trem2 expression on DMs following T. gondii infection. By using a knockout mouse model, we found that Trem2-deficiency resulted in more severe adverse pregnancy outcomes as compared to the mock controls. Additionally, compelling evidence from animal models and in vitro cell experiments indicated that T. gondii downregulated PPARγ and phosphorylated-STAT6 (P-STAT6). In addition, Trem2-deficiency led to weakened macrophage responses to T. gondii antigens (TgAg) in both peritoneal macrophages and bone marrow-derived macrophages (BMDMs). Consistently, overexpression of Trem2 in macrophages significantly activated the downstream signaling pathway and partially reversed the inhibitory effects of TgAg on P-STAT6 and PPARγ, similar to the effect of PPARγ agonists. Altogether, our study identified Trem2 as a key factor implicated in the pathomechanism of adverse pregnancy outcomes due to T. gondii infection. Our novel findings in regard to Trem2 and its downstream PPARγ and STAT6 signaling pathways might provide new preventive and therapeutic targets for toxoplasmosis.