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Published on: November 19, 2010
Enhanced M-CSF/CSF1R Signaling Closely Associates with PrPSc Accumulation in the Scrapie-Infected Cell Line and the
Ying Xia1, Cao Chen2,3, Jia Chen1
1State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), Chinese Center for Disease Control and Prevention, National Institute for Viral Disease Control and Prevention, Beijing, China.
Abstract:
Activation and proliferation of microglia are one of the hallmarks of prion disease and is usually accompanied by increased levels of various cytokines and chemokines. Our previous study demonstrated that the level of brain macrophage colony-stimulating factor (M-CSF) was abnormally elevated during prion infection, but its association with PrPSc is not completely clear. In this study, colocalization of the increased M-CSF with accumulated PrPSc was observed by IHC with serial brain sections. Reliable molecular interaction between total PrP and M-CSF was observed in the brain of 263 K-infected hamsters and in cultured prion-infected cell line. Immunofluorescent assays showed that morphological colocalization of M-CSF with neurons and microglia, but not with astrocytes in brains of scrapie-infected animals. The transcriptional and expressing levels of CSF1R were also significantly increased in prion-infected cell line and mice, and colocalization of CSF1R with neurons and microglia was observed in the brains of prion-infected mouse models. Removal of PrPSc replication by resveratrol in SMB-S15 cells induced limited reductions of cellular levels of M-CSF and CSF1R. In addition, we found that the level of IL-34, another ligand of CSF1R, did not change significantly after prion infection, but its distribution on the cell types in the brains shifted from neurons in healthy mice to the proliferated astrocytes and microglia in scrapie-infected mice. Our data demonstrate activation of M-CSF/IL-34/CSF1R signaling in the microenvironment of prion infection, strongly indicating its vital role in the pathophysiology of prions. It provides solid scientific evidence for the therapeutic potential of inhibiting M-CSF/CSF1R signaling in prion diseases.
Insights
Macrophage colony-stimulating factor (M-CSF) and its receptor CSF1R are activated in prion diseases, interacting with PrPSc. This M-CSF/IL-34/CSF1R signaling pathway is vital for prion pathophysiology and offers therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Prion Biology
Background:
- Microglial activation is a hallmark of prion diseases, associated with cytokine and chemokine increases.
- Brain macrophage colony-stimulating factor (M-CSF) is elevated in prion infection, but its link to PrPSc requires clarification.
Purpose of the Study:
- To investigate the role and interactions of M-CSF and its receptor CSF1R in prion disease pathogenesis.
- To explore the therapeutic potential of targeting the M-CSF/CSF1R signaling pathway.
Main Methods:
- Immunohistochemistry (IHC) and immunofluorescent assays to assess colocalization of M-CSF, PrPSc, and CSF1R in infected brains and cell lines.
- Analysis of gene and protein expression levels of M-CSF and CSF1R.
- Investigation of IL-34 distribution in prion-infected models.
Main Results:
- M-CSF colocalizes with PrPSc in prion-infected brains and cell lines.
- CSF1R expression and levels are significantly increased in prion-infected models and colocalize with neurons and microglia.
- IL-34 distribution shifts to astrocytes and microglia in infected brains, while M-CSF/CSF1R signaling is activated.
Conclusions:
- The M-CSF/IL-34/CSF1R signaling pathway is activated in the prion infection microenvironment.
- This pathway plays a crucial role in prion disease pathophysiology.
- Inhibiting M-CSF/CSF1R signaling presents a potential therapeutic strategy for prion diseases.
