Toxoplasma gondii-induced adverse pregnancy outcomes: insight into the inhibitory role of Trem2 on TLR4/TRAF6/JNK signaling pathway
Description
Decidual macrophages (dMφs) are not only essential for maintaining normal pregnancy but also serve as crucial immune defenders against infections, including Toxoplasma gondii (T. gondii). Triggering receptor expressed on myeloid cells 2 (Trem2), as a critical immunoregulatory receptor on dMφs, can counteract inflammation and defend against pathogen infection. However, the mechanisms underlying the Trem2 downstream pathways during T. gondii infection—particularly their impact on adverse pregnancy outcomes (APOs)—remain elusive. Here, via establishing T. gondii-challenged wild type and Trem2-/- mouse pregnancy models, we observed that genetic ablation of Trem2 exacerbated T. gondii-triggered APOs. Importantly, the interaction of Trem2 with Toll-like receptor 4 (TLR4) was predicated by molecular docking models with a calculated binding energy (-15 kcal/mol) and confirmed by co-IP. Both animal and cellular models were employed, revealing that Trem2 downregulation in the response to T. gondii, concomitant with an increase in TLR4 and its downstream signaling molecules like TNF receptor-associated factor 6 (TRAF6) and c-Jun N-terminal kinase (JNK). More importantly, Trem2 deficiency in mice and macrophages further enhanced the activation of TLR4/TRAF6/JNK signaling axis. In contrast, Trem2 overexpression in macrophages inhibited the expression of the downstream signaling cascade and reversed the activation induced by T. gondii antigens. Additionally, the treatment with a TLR4-blocking antibody suppressed the activation of TRAF6 and P-JNK in both Raw 264.7 cells and bone marrow-derived macrophages stimulated with T. gondii antigens, whereas it failed to inhibit Trem2 expression. Taken together, Trem2 deficiency in mice promotes the TLR4/TRAF6/JNK signaling cascade, contributing to exacerbate APOs following T. gondii infection. This study provides novel mechanistic insights into T. gondii-induced pregnancy outcomes, highlighting the pregnancy-specific inhibitory function of Trem2 on TLR4/TRAF6/JNK signaling pathway.