Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration

Beatrice Paola Festa, Farah H. Siddiqi, Maria Jimenez-Sanchez, Hyeran Won, Matea Rob, Alvin Djajadikerta, Eleanna Stamatakou, David C. Rubinsztein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2021-2037.e12
JournalNeuron
Volume111
Issue number13
Early online date26 Apr 2023
DOIs
Publication statusPublished - 5 Jul 2023

Keywords

  • autophagy
  • CCL5
  • CCR5
  • dementia
  • Huntington's disease
  • maraviroc
  • microglia
  • mTORC1
  • neuroinflammation
  • Tau

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