The Innate Immune Sensor Zbp1 Mediates Central Nervous System Inflammation Induced by Angiostrongylus Cantonensis by Promoting Macrophage Inflammatory Phenotypes

Abstract Angiostrongylus cantonensis (AC) is the leading cause of eosinophilic meningoencephalitis worldwide. The neuroimmune interactions between peripheral and central immune systems in angiostrongyliasis remain unclear. In this study, significant infiltration of eosinophils, myeloid cells, macrophages, neutrophils, and Ly6C monocytes is observed in the brains of AC‐infected mice, with macrophages being the most abundant. RNA‐seq and SMART‐seq analysis of pattern recognition receptor (PRR) and DNA sensor gene sets revealed a marked increase in Z‐DNA binding protein 1 (Zbp1) expression in infected mice. Confocal microscopy, RT‐qPCR, western blotting, and immunohistochemistry further confirmed that Zbp1 is specifically upregulated in macrophages and microglia. Using Zbp1‐knockout mice and flow cytometry, it is found that knockout of Zbp1 enhanced lymphocyte infiltration and natural killer cell cytotoxicity, modulating the immune microenvironment in the central nervous system (CNS) during AC infection. Mechanistically, it is revealed that in macrophage Zbp1 directly binds to receptor‐interacting protein 3 (RIP3) to promote its phosphorylation, subsequently facilitating the phosphorylation of mixed lineage kinase domain‐like protein (Mlkl). The activated Zbp1‐pRIP3‐pMlkl axis leads to necroptosis and upregulates pro‐inflammatory cytokines including TNF‐α, IL‐1α, CXCL9, CXCL10 in macrophages, which recruits and activates immune cells. These findings offer new insights into the pathogenic mechanisms of angiostrongyliasis and suggest potential therapeutic strategies.