Remote Postischemic Conditioning Promotes Stroke Recovery by Shifting Circulating Monocytes to CCR2+ Proinflammatory Subset

Research output: Contribution to journalArticle

Authors

  • Jiwon Yang
  • Mustafa Balkaya
  • Cesar Beltran
  • Ji Hoe Heo
  • Sunghee Cho

External Institution(s)

  • Burke Neurological Institute
  • Yonsei University
  • Weill Cornell Medical College

Details

Original languageEnglish (US)
Pages (from-to)7778-7789
Number of pages12
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume39
Issue number39
StatusPublished - Sep 25 2019
Peer-reviewedYes

Abstract

Brain injury from stroke is typically considered an event exclusive to the CNS, but injury progression and repair processes are profoundly influenced by peripheral immunity. Stroke stimulates an acute inflammatory response that results in a massive infiltration of peripheral immune cells into the ischemic area. While these cells contribute to the development of brain injury, their recruitment has been considered as a key step for tissue repair. The paradoxical role of inflammatory monocytes in stroke raises the possibility that the manipulation of peripheral immune cells before infiltration into the brain could influence stroke outcome. One such manipulation is remote ischemic limb conditioning (RLC), which triggers an endogenous tolerance mechanism. We observed that mice subjected to poststroke RLC shifted circulating monocytes to a CCR2+ proinflammatory monocyte subset and had reduced acute brain injury, swelling, and improved motor/gait function in chronic stroke. The RLC benefits were observed regardless of injury severity, with a greater shift to a CCR2+ subset in severe stroke. Adoptive transfer of CCR2-deficient monocytes abolished RLC-mediated protection. The study demonstrates the importance of RLC-induced shift of monocytes to a CCR2+ proinflammatory subset in attenuating acute injury and promoting functional recovery in chronic stroke. The defined immune-mediated mechanism underlying RLC benefits allows for an evidence-based framework for the development of immune-based therapeutic strategies for stroke patients.SIGNIFICANCE STATEMENT Stroke is the leading cause of physical disability worldwide but has few treatment options for patients. Because remote ischemic limb conditioning (RLC) elicits endogenous tolerance in neither an organ- nor a tissue-specific manner, the immune system has been considered a mediator for an RLC-related benefit. Application of RLC after stroke increased a proinflammatory CCR2+ monocyte subset in the blood and the brain. RLC reduced acute stroke injury and promoted motor/gait function during the recovery phase. The RLC benefits were absent in mice that received CCR2-deficient monocytes. This preclinical study shows the importance of CCR2+ proinflammatory monocytes in RLC benefits in stroke and provides a therapeutic RLC platform as a novel immune strategy to improve outcomes in stroke patients.

    Research areas

  • CCR2, inflammation, ischemic stroke, monocyte, recovery, remote ischemic limb conditioning

Citation formats

APA

Yang, J., Balkaya, M., Beltran, C., Heo, J. H., & Cho, S. (2019). Remote Postischemic Conditioning Promotes Stroke Recovery by Shifting Circulating Monocytes to CCR2+ Proinflammatory Subset. The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(39), 7778-7789. https://doi.org/10.1523/JNEUROSCI.2699-18.2019

Harvard

Yang, J, Balkaya, M, Beltran, C, Heo, JH & Cho, S 2019, 'Remote Postischemic Conditioning Promotes Stroke Recovery by Shifting Circulating Monocytes to CCR2+ Proinflammatory Subset', The Journal of neuroscience : the official journal of the Society for Neuroscience, vol. 39, no. 39, pp. 7778-7789. https://doi.org/10.1523/JNEUROSCI.2699-18.2019