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

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

doi:10.3967/bes2024.158

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

Biomed Environ Sci. 2024 Nov 20;37(11):1235-1251. doi: 10.3967/bes2024.158.

Authors

Chen Jia¹, Chen Cao², Hu Chao¹, Yang Wei¹, Wang Lin¹, Chen Dongdong¹, Wu Yuezhang¹, Shi Qi³, Dong Xiaoping⁴

Affiliations

¹ National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory for Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.
² National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory for Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China;Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 100084, Zhejiang, China;Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, Hubei, China.
³ National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory for Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China;Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 100084, Zhejiang, China;China Academy of Chinese Medical Sciences, Beijing 100700, China.
⁴ National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory for Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China;Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 100084, Zhejiang, China;Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, Hubei, China;China Academy of Chinese Medical Sciences, Beijing 100700, China;Shanghai Institute of Infectious Disease and Biosafety, Shanghai 200003, China.

PMID: 39667961
DOI: 10.3967/bes2024.158

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.

Keywords: Activation; CXCR3; Chemokine; IP10; Prion.

MeSH terms

Animals
Brain* / metabolism
Chemokine CXCL10* / metabolism
Mice
PrPSc Proteins* / metabolism
Receptors, CXCR3* / metabolism
Scrapie* / metabolism
Signal Transduction*

Substances

Receptors, CXCR3
Chemokine CXCL10
PrPSc Proteins
Cxcr3 protein, mouse
Cxcl10 protein, mouse