CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury

• Published in: Cell Vol. 176; no. 5; pp. 1143 - 1157.e13
• Main Authors: Joy, Mary T., Ben Assayag, Einor, Shabashov-Stone, Dalia, Liraz-Zaltsman, Sigal, Mazzitelli, Jose, Arenas, Marcela, Abduljawad, Nora, Kliper, Efrat, Korczyn, Amos D., Thareja, Nikita S., Kesner, Efrat L., Zhou, Miou, Huang, Shan, Silva, Tawnie K., Katz, Noomi, Bornstein, Natan M., Silva, Alcino J., Shohami, Esther, Carmichael, S. Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.02.2019
• Subjects: Aged; Aged, 80 and over; Animals; astrocyte; axon; axonal sprouting; Brain Injuries, Traumatic - therapy; Cyclic AMP Response Element-Binding Protein - metabolism; dendritic spine; Dendritic Spines - metabolism; Disease Models, Animal; Female; Humans; Male; Mice, Inbred C57BL; microglia; Middle Aged; MOCA; motor; Motor Cortex - metabolism; Neuronal Plasticity - physiology; Neurons - metabolism; NIHSS; premotor; Receptors, CCR5 - metabolism; Receptors, CCR5 - physiology; Stroke - therapy; Stroke Rehabilitation - methods; NIHSS; motor; axonal sprouting; MOCA; premotor; dendritic spine; axon; astrocyte; microglia
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.01.044

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke. [Display omitted] •CCR5 is differentially upregulated in neurons after stroke•Knockdown of CCR5 induces motor recovery after stroke and improves cognition after TBI•Treatment with an FDA-approved drug, maraviroc induces recovery after stroke and TBI•Human carriers for CCR5delta32 have better outcomes after stroke Genetic and small molecule-based perturbation of CCR5 promotes functional recovery from stroke and traumatic brain injury.