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Microglial Cx3cr1 knockout reduces prion disease incubation time in mice
Julia Grizenkova, Shaheen Akhtar, Sebastian Brandner
1MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. s.lloyd@prion.ucl.ac.uk.
Background:
Microglia are resident mononuclear phagocytes of the brain that become activated in response to insults including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and prion disease. In the central nervous system the chemokine Cx3cl1 (Fractalkine) is expressed by neurons and its exclusive receptor Cx3cr1 is expressed solely on microglia. Cx3cl1/Cx3cr1 signalling is thought to maintain microglia in their resting state and disrupting this equilibrium may allow microglia to become activated. In prion disease, microglial proliferation has been suggested to contribute to overall disease progression, however, in different mouse models of neurodegeneration, loss of Cx3cr1 has been shown to either worsen or improve the phenotype depending on the paradigm.
Results:
To investigate the role of Cx3cl1/Cx3cr1 signalling in prion disease we infected Cx3cr1 null mice with three different strains of prions. Following challenge with Chandler/RML, ME7 and MRC2 prion strains, Cx3cr1 knockout mice showed highly significant reductions in incubation time. No differences were seen in the pattern and localisation of activated microglia in the brain or in the mRNA expression levels of chemokines/cytokines (Cxcl10, Il-12b, Il-1b, Arg-1 and Cxc3l1).
Conclusion:
Our data suggest a protective role for Cx3cl1/Cx3cr1 cross-talk in prion disease.
Insights
The CX3CL1/CX3CR1 pathway may protect against prion disease. Loss of CX3CR1 signaling in microglia accelerated disease progression in mouse models, suggesting a therapeutic target.
Area of Science:
- Neuroimmunology
- Neurodegenerative Diseases
- Prion Biology
Background:
- Microglia, the brain's immune cells, activate in response to neurodegeneration.
- CX3CL1 (Fractalkine) signaling via its receptor CX3CR1 on microglia is crucial for maintaining their resting state.
- Disruption of this signaling may lead to microglial activation and influence disease progression.
Purpose of the Study:
- To investigate the role of CX3CL1/CX3CR1 signaling in prion disease pathogenesis.
- To determine the effect of CX3CR1 deficiency on prion disease progression in mice.
Main Methods:
- Infection of CX3CR1 knockout mice with three distinct prion strains (Chandler/RML, ME7, MRC2).
- Monitoring of disease incubation times.
- Analysis of microglial activation patterns and cytokine/chemokine mRNA expression.
Main Results:
- CX3CR1 knockout mice exhibited significantly shorter incubation times across all prion strains tested.
- No significant differences were observed in the localization or pattern of activated microglia.
- No changes in the mRNA expression levels of key inflammatory markers were detected.
Conclusions:
- CX3CL1/CX3CR1 signaling appears to play a protective role in prion disease.
- Loss of this signaling pathway accelerates prion disease progression in mice.
