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

Cell. 2019 Feb 21;176(5):1143-1157.e13. doi: 10.1016/j.cell.2019.01.044.

Abstract

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.

Keywords: MOCA; NIHSS; astrocyte; axon; axonal sprouting; dendritic spine; microglia; motor; premotor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Brain Injuries, Traumatic / therapy*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Motor Cortex / metabolism
  • Neuronal Plasticity / physiology
  • Neurons / metabolism
  • Receptors, CCR5 / metabolism*
  • Receptors, CCR5 / physiology
  • Stroke / therapy*
  • Stroke Rehabilitation / methods

Substances

  • CCR5 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Receptors, CCR5