Toxoplasma gondii-induced adverse pregnancy outcomes: insight into the inhibitory role of Trem2 on TLR4/TRAF6/JNK signaling pathway.

BACKGROUND

Decidual macrophages (dMφs) are not only essential for maintaining normal pregnancy but also serve as crucial immune defenders against infections, including Toxoplasma 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.

METHODS

The interaction between Trem2 and Toll-like receptor 4 (TLR4) was initially predicted through molecular docking models and subsequently confirmed by co-immunoprecipitation, using both animal models and cellular systems to examine the impact of Trem2 knockout, overexpression, and TLR4-blocking antibody treatment on downstream signaling molecules as well as cytokine production.

RESULTS

The interaction between Trem2 and TLR4 was validated. Trem2 downregulation during T. gondii infection coincided with increased TLR4, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), and c-Jun N-terminal kinase (JNK) activation, while Trem2 knockout further enhanced TLR4/TRAF6/JNK signaling in mice and macrophages. Conversely, Trem2 overexpression suppressed this signaling cascade and reversed T. gondii-induced activation. Treatment with a TLR4-blocking antibody inhibited TRAF6 and P-JNK activation in macrophages but did not affect Trem2 expression. Additionally, Trem2-deficient bone marrow-derived macrophages (BMDMs) exhibited elevated transcription of TNF-α and interferon-γ (IFN-γ) upon T. gondii antigen stimulation.

CONCLUSIONS

Trem2 deficiency in pregnant mice promotes the TLR4/TRAF6/JNK signaling cascade following T. gondii infection. This study demonstrates that Trem2 acts as a pregnancy-specific inhibitor of TLR4/TRAF6/JNK signaling, providing novel mechanistic insights into T. gondii-induced APOs.