Activation of IP10/CXCR3 signaling is highly coincidental with the deposition of PrPSc in the brains of scrapie-infected mice

Abstract

Abstract The chemokine IP10 and its receptor CXCR3 are activated in CNS during various neurodegenerative diseases. Our previous study demonstrated elevated levels of IP10 in the brains of several scrapie rodent models. However, the precise modulation of IP10/CXCR3 signaling in CNS during prion infection remains unresolved. Here, we observed an upregulation of IP10 signals primarily localized in neurons within the brains of scrapie-infected mice using various methodologies. Both CXCR3 levels and activation were significantly increased in the brains of scrapie-infected mice and in the prion-infected cell line SMB-S15. Enhanced CXCR3 expression was predominantly observed in neurons and activated microglia. Morphological colocalizations of PrPC/PrPSc with IP10 and CXCR3 were observed in the brains of scrapie-infected mice through IHC and immunofluorescence. IHC analysis using whole brain sections revealed increased accumulation of IP10 and CXCR3 specifically occurred in brain regions with higher levels of PrPSc deposits. Co-immunoprecipitation and biomolecular interaction assays suggested molecular interactions of PrP and IP10 as well as CXCR3. Notably, a significantly larger amount of IP10 accumulated within prion-infected SMB-S15 cells compared to the normal partner cell line SMB-PS. Importantly, treatment with resveratrol effectively suppressed prion replication in SMB-S15 cells, restoring the pattern of accumulation and secretion of cellular IP10 similar to that observed in SMB-PS cells. Our data presented herein demonstrate the activation of IP10/CXCR3 signaling in prion-infected brain tissues coinciding with the deposition of PrPSc. Modulating IP10/CXCR3 signaling in the brain represents a potential therapeutic target for mitigating the progression of prion diseases.