CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury
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 contro...
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Published in | Cell Vol. 176; no. 5; pp. 1143 - 1157.e13 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
21.02.2019
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conception and design of work, S.T.C., M.T.J., A.J.S., and E.S.; data collection, M.T.J., E.B.A., D.S.-S., S.L.-Z., N.A., N.S.T., M.A., E.K., E.L.K., S.H., M.Z., T.K.S., N.K., and E.S.; data analysis and interpretation, M.T.J., E.B.A., D.S.-S., S.L.-Z., J.M., M.A., E.K., E.L.K., N.K., A.J.S., E.S., and S.T.C.; drafting the article, M.T.J., S.T.C., E.B.A., E.S., A.D.K., and N.M.B.; critical revision of the article, S.T.C., M.T.J., E.B.A., E.S., A.J.S., and A.D.K. All authors have agreed on the final version to be published. |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2019.01.044 |