Pharmacological modulation of CXCL12/CXCR4/ACKR3 for brain disorders - an overview.

Chemokines are small molecules that regulate many essential biological processes by guiding oriented cell movement. The chemokine CXCL12 and its two receptors, CXCR4 and ACKR3, are crucial in tissue development and balance. In the central nervous system (CNS), dysregulation of this signaling axis leads to the development of various pathologies including Alzheimer’s and Parkinson’s diseases, multiple sclerosis, amyotrophic lateral sclerosis or brain cancer. As a consequence, several drugs targeting CXCL12, CXCR4 or ACKR3 have been developed aiming at treating such diseases. Here, we sum up current knowledge regarding the molecular mechanisms of CXCL12/CXCR4/ACKR3 signaling and the role of this pathway in the brain, under normal and diseased conditions. We also summarize and discuss the effect of pharmacological modulators in various contexts, from their early development to their validation in experimental models and human patients.