Related Experiment Video
Updated: Aug 1, 2025
In vitro Quantitative Imaging Assay for Phagocytosis of Dead Neuroblastoma Cells by iPSC-Macrophages
Published on: February 14, 2021
Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration
Beatrice Paola Festa1, Farah H Siddiqi1, Maria Jimenez-Sanchez2
1Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), CB2 0XY Cambridge, UK; UK Dementia Research Institute, Cambridge Institute for Medical Research (CIMR), CB2 0XY Cambridge, UK.
Abstract:
In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy, a degradative pathway critical for the removal of toxic, aggregate-prone proteins accumulating in neurodegenerative diseases. We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington's disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models.
Insights
Activated microglia release inflammatory factors that impair neuronal autophagy, hindering the clearance of toxic proteins in neurodegenerative diseases like Huntington's disease. Inhibiting the CCL-3/-4/-5 and CCR5 pathway restores autophagy and ameliorates disease pathology.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Neurodegenerative diseases feature activated microglia secreting pro-inflammatory factors.
- Microglial activation impairs neuronal autophagy, a key pathway for clearing toxic protein aggregates.
- This process is critical for understanding and treating diseases like Huntington's and tauopathy.
Purpose of the Study:
- To investigate how microglial paracrine signaling affects neuronal function in neurodegenerative diseases.
- To identify the specific molecular mechanisms by which microglia inhibit neuronal autophagy.
- To explore the therapeutic potential of targeting this microglia-neuronal axis.
Main Methods:
- Investigated the role of microglial-derived chemokines (CCL-3/-4/-5) and neuronal receptors (CCR5) in autophagy regulation.
- Utilized pre-manifesting mouse models for Huntington's disease and tauopathy.
- Employed pharmacological and genetic inhibition of the CCR5 pathway.
Main Results:
- Activated microglia inhibit neuronal autophagy via the CCL-3/-4/-5 binding to neuronal CCR5, promoting mTORC1 activation.
- CCR5 and its chemokines are upregulated in early stages of Huntington's disease and tauopathy mouse models.
- CCR5 upregulation is self-sustaining, and its inhibition rescues autophagy and ameliorates disease pathology in mouse models.
Conclusions:
- A novel microglia-neuronal communication axis involving CCL-3/-4/-5 and CCR5 plays a pathological role in early neurodegeneration.
- Targeting the CCR5 pathway can restore neuronal autophagy and mitigate Huntington's disease and tauopathy.
- This axis represents a promising therapeutic target for neurodegenerative diseases.
