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 aCCR2+proinflammatory monocyte subset and had reduced acute brain injury, swelling, and improved motor/gait function in chronic stroke. TheRLCbenefits 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.
Bibliographical noteFunding Information:
Received Oct. 18, 2018; revised June 17, 2019; accepted July 26, 2019. Authorcontributions:J.Y.andS.C.designedresearch;J.Y.,M.B.,andC.B.performedresearch;J.Y.analyzeddata; J.Y. wrote the first draft of the paper; J.Y., M.B., J.H.H., and S.C. edited the paper; J.Y. and S.C. wrote the paper. This work was supported by National Institutes of Health Grants HL082511, NS095359, and NS077897 to S.C., National Research Foundation of Korea funded by the Ministry of Education Basic Science Research Program 2013R1A6A3A03059436 to J.Y., and American Heart Association Postdoctoral Fellowship 15POST25680020 to J.Y. We thank Dr. John Cave for comments and editorial assistance; and Dr. Yang Guo for technical assistance. The authors declare no competing financial interests. Correspondence should be addressed to Sunghee Cho at email@example.com. J. Yang’s present address: The Jackson Laboratory, 1650 Santa Ana Avenue, Sacramento, CA 95838.
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