State reproductive rights policies and unintended pregnancy.

A widely prevalent zoonotic pathogen, () poses a particularly serious threat to pregnancy health (). During early pregnancy, the maternal body is in a physiologically immunocompromised state to maintain maternal-fetal tolerance, facilitating embryo implantation and development (; ). This state makes pregnant women susceptible to vertical transmission of the pathogen through the placenta upon infection, leading to congenital toxoplasmosis, which clinically manifests as miscarriage, fetal developmental abnormalities, or stillbirth (; ). Findings indicate that primarily exerts its pathogenic effects by successfully breaking down the normally sustained immune tolerance equilibrium between mother and fetus (; ). As the key regulatory cells at this interface, decidual macrophages control embryo implantation, induce immune tolerance, and modulate inflammation by undergoing phenotypic polarization and functional conversion (; ). Previous reports indicate that directly modulates decidual macrophage activity through the secretion of various effector molecules (; ). For instance, the dense granule protein 28 (GRA28) regulates the secretion of C-C motif chemokine ligand 22 (CCL22) from trophoblast cells via the myc regulation 1 (MYR1) axis, contributing to miscarriage (). On the other hand, dense granule protein 15 (GRA15) drives the expression of pro-inflammatory cytokines (e.g., IL-1β and IL-12), triggers the NF-κB signaling cascade, and shifts macrophage polarization toward an M1-like state (). Concurrently, research has also found that abundant IL-10 secreted by M2-polarized decidual macrophages helps protect against adverse pregnancy complications (APC) resulting from infection (). This evidence suggests that infection likely disrupts tolerance between mother and fetus by secreting effector molecules that manipulate decidual macrophage function, ultimately leading to APC. Therefore, this study sought to elucidate the key host protective molecule and its downstream signaling cascade involved in preserving decidual macrophage function during infection. Expressed broadly on myeloid cells, Trem2 (triggering receptor expressed on myeloid cells 2) is a surface receptor that critically regulates multiple cellular functions, including survival, migration, phagocytosis, and cytokine secretion (; ; ). Researchers comparing decidual macrophages with peripheral blood CD14 cells have identified Trem2 as one of the characteristically highly expressed genes in decidual macrophages, constituting its immunoregulatory phenotype along with M2-type markers such as CCL-18 and CD209 (). Meanwhile, single-cell transcriptomic analyses of placentas from preeclampsia cases have also revealed Trem2 macrophages as major participants in the placental immune niche (; ). Importantly, Trem2 not only directly regulates macrophages but also suppresses inflammatory responses through its downstream signaling pathways (). For example, Trem2 disrupts glycolysis via the JAK2/STAT3 axis, thereby inhibiting M1 polarization and inflammation (). However, this protective mechanism becomes markedly disrupted when infection occurs. We previously reported that infection downregulates Trem2 expression, consequently disrupting the M1/M2 balance and creating a pro-inflammatory milieu across the maternal-fetal interface (). Emerging evidence indicates that MTOR is a key regulator of macrophage function and maternal-fetal immune homeostasis (). In addition, can manipulate host MTOR signaling to facilitate intracellular survival (). Nevertheless, although both Trem2 and MTOR have independently been implicated in macrophage biology, pregnancy-associated immune regulation, and infection, whether Trem2 directly regulates MTOR signaling in decidual macrophages, and whether disruption of this regulatory axis contributes to APC following infection, remain largely unknown. Based on this, the present study first confirmed the potential interaction between Trem2 and MTOR through bioinformatic prediction and co-immunoprecipitation, and precisely identified the key binding sites using alanine scanning mutagenesis. Both cell-based and animal studies demonstrated that infection significantly reduced Trem2 expression while upregulating MTOR and its downstream effector Protein kinase C alpha (PKCα). In summary, this study reveals for the first time that Trem2 acts as a negative regulator of MTOR, suppressing MTOR expression through direct interaction and subsequently downregulating downstream PKCα signaling. infection, by downregulating Trem2, leads to hyperactivation of the MTOR-PKCα axis, ultimately driving M1/M2 imbalance in decidual macrophages and APC. This discovery provides a new understanding of immunopathological mechanisms of toxoplasmosis and lays a theoretical foundation for developing intervention strategies for infection during pregnancy.