TLR9/NF-κB-Mediated Dendritic Cell Activation by Neutrophil Extracellular Traps Drives Pathogenesis in Experimental Cerebral Malaria

Cerebral malaria (CM), the most severe complication of Plasmodium infection, accounts for the majority of malaria-associated mortality. The experimental cerebral malaria (ECM) model, recapitulating key neuropathological features of human CM, provides critical insights into disease mechanisms. While neutrophils demonstrate dual roles in Plasmodium control and immunopathology, their early dynamics in ECM remain unclear. Here, we found that early neutrophil depletion in Plasmodium berghei ANKA (PbA)-infected mice significantly prolongs survival, preserves blood-brain barrier integrity, and reduces brain infiltration and activation of CD8⁺ T cells. Mechanistically, PbA infection induces neutrophil extracellular traps (NETs) formation. The DNA component of NETs activates dendritic cells (DCs) through the TLR9/NF-κB signaling pathway, leading to upregulated expression of costimulatory molecules and proinflammatory cytokines that potentiate CD8⁺ T cell effector functions. Inhibition of NET formation alleviates ECM progression. These findings establish the critical role of the NETs-TLR9-NF-κB-DC-CD8⁺ T cell axis in ECM pathogenesis, providing novel insights into the immunopathogenic mechanisms of CM.