Activation of IP10/CXCR3 Signaling is Highly Coincidental with PrP ^Sc Deposition in the Brains of Scrapie-Infected Mice.

Biomedical and environmental sciences : BES Pub Date : 2024-11-20 DOI:10.3967/bes2024.158

Chen Jia, Chen Cao, Hu Chao, Yang Wei, Wang Lin, Chen Dongdong, Wu Yuezhang, Shi Qi, Dong Xiaoping

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Abstract

Objective: To analyze the relationship between Chemokine IP10 and its receptor CXCR3 during prion infection.

Methods: We investigated the increases in IP10 signals, primarily localized in neurons within the brains of scrapie-infected mice, using western blotting, ELISA, co-immunoprecipitation, immunohistochemistry, immunofluorescence assays, and RT-PCR.

Results: Both CXCR3 levels and activation were significantly higher in the brains of scrapie-infected mice and prion-infected SMB-S15 cells. Enhanced CXCR3 expression was predominantly observed in neurons and activated microglia. Morphological colocalization of PrP ^C/PrP ^Sc with IP10/CXCR3 was observed in scrapie-infected mouse brains using immunohistochemistry and immunofluorescence. immunohistochemistry (IHC) analysis of whole brain sections further revealed increased accumulation of IP10/CXCR3 specifically in brain regions with higher levels of PrP ^Sc deposits. Co-immunoprecipitation and biomolecular interaction assays revealed the molecular interactions between PrP and IP10/CXCR3. Notably, a significantly larger amount of IP10 accumulated within prion-infected SMB-S15 cells than in the normal partner cell line, SMB-PS. Importantly, resveratrol treatment effectively suppressed prion replication in SMB-S15 cells, thereby restoring the accumulation and secretion pattern of cellular IP10 similar to that observed in SMB-PS cells.

Conclusion: Our data demonstrate that the activation of IP10/CXCR3 signaling in prion-infected brain tissues coincides with PrP ^Sc deposition. Modulation of IP10/CXCR3 signaling in the brain represents a potential therapeutic target for mitigating the progression of prion diseases.

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