TLR2-Driven NLRP3 Inflammasome Activation Mediates EV71-Induced Neuropathogenesis in Neonatal Mice

EV71 is a leading cause of HFMD-associated neurological complications, yet its CNS pathogenic mechanisms remain unclear. Using neonatal BALB/c mice, we identified 10 days post-infection (dpi) as the disease peak, characterized by neuronal necrosis and robust NLRP3 inflammasome activation. We demonstrate that EV71 upregulates TLR2, triggering the NF-κB pathway to prime and activate the NLRP3 inflammasome within microglia. This process drives pro-inflammatory cytokine release and neuroinflammatory damage. Pharmacological blockade of TLR2 with C29 suppressed NF-κB phosphorylation and NLRP3 assembly, reducing viral accumulation by improving the neuroinflammatory microenvironment rather than through direct antiviral activity. Furthermore, the NLRP3 inhibitor MCC950 significantly attenuated clinical symptoms, reduced neuronal apoptosis, and improved survival rates. In summary, our findings identify the TLR2-NF-κB-NLRP3 signaling axis as a central driver of EV71-induced neuroinflammation. This cascade represents a promising host-directed therapeutic target for mitigating the neurological sequelae associated with EV71 infection.