Microglial cytokines poison neuronal autophagy via CCR5, a druggable target

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.

Automated summary

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.