4.8 Article

Microglial cytokines poison neuronal autophagy via CCR5, a druggable target

Journal

AUTOPHAGY
Volume -, Issue -, Pages -

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2023.2221921

Keywords

CCR5; Huntington disease; Tau; autophagy; maraviroc; microglia

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In the prodromal phase of neurodegenerative diseases, microglia switch to an activated state and secrete pro-inflammatory factors. These factors, namely CCL3, CCL4, and CCL5, inhibit neuronal autophagy through CCR5 activation, leading to the accumulation of aggregate-prone proteins in neurons. Increased levels of CCR5 and its chemokine ligands are observed in pre-manifesting Huntington disease and tauopathy mouse models. Inhibiting CCR5 rescues mTORC1-autophagy dysfunction and improves neurodegeneration, indicating that CCR5 hyperactivation drives the progression of these diseases.
In the prodromal phase of neurodegenerative diseases, microglia switch to an activated state resulting in increased secretion of pro-inflammatory factors. We reported that C - C chemokine ligand 3 (CCL3), C - C chemokine ligand 4 (CCL4) and C - C chemokine ligand 5 (CCL5) contained in the secretome of activated microglia inhibit neuronal autophagy via a non-cell autonomous mechanism. These chemokines bind and activate neuronal C - C chemokine receptor type 5 (CCR5), which, in turn, promotes phosphoinositide 3-kinase (PI3K) - protein kinase B (PKB, or AKT) - mammalian target of rapamycin complex 1 (mTORC1) pathway activation, which inhibits autophagy, thus causing the accumulation of aggregate-prone proteins in the cytoplasm of neurons. The levels of CCR5 and its chemokine ligands are increased in the brains of pre-manifesting Huntington disease (HD) and tauopathy mouse models. CCR5 accumulation might be due to a self-amplifying mechanism, since CCR5 is a substrate of autophagy and CCL5-CCR5-mediated autophagy inhibition impairs CCR5 degradation. Furthermore, pharmacological, or genetic inhibition of CCR5 rescues mTORC1-autophagy dysfunction and improves neurodegeneration in HD and tauopathy mouse models, suggesting that CCR5 hyperactivation is a pathogenic signal driving the progression of these diseases.

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