Remote limb ischemic postconditioning protects against ischemic stroke by promoting regulatory t cells thriving

Hai Han Yu, Xiao Tong Ma, Xue Ma, Man Chen, Yun Hui Chu, Long Jun Wu, Wei Wang, Chuan Qin, Dai Shi Tian

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Remote limb ischemic postconditioning (RLIPoC) has been demonstrated to protect against ischemic stroke. However, the underlying mechanisms of RLIPoC mediating cross-organ protection remain to be fully elucidated. METHODS AND RESULTS: Ischemic stroke was induced by middle cerebral artery occlusion for 60 minutes. RLIPoC was performed with 3 cycles of 10-minute ischemia followed by 10-minute reperfusion of the bilateral femoral arteries im-mediately af ter middle cerebral artery reperfusion. The percentage of regulatory T cells ( Tregs) in the spleen, blood, and brain was detected using flow cytometry, and the number of Tregs in the ischemic hemisphere was counted using transgenic mice with an enhanced green fluorescent protein-tagged Foxp3. Furthermore, the metabolic status was monitored dynamically using a multispectral optical imaging system. The Tregs were conditionally depleted in the depletion of Treg transgenic mice af ter the injection of the diphtheria toxin. The inflammatory response and neuronal apoptosis were investigated using immunofluorescent staining. Infarct volume and neurological deficits were evaluated using magnetic resonance imaging and the modified neurological severity score, respectively. The results showed that RLIPoC substan-tially reduced infarct volume, improved neurological function, and significantly increased Tregs in the spleen, blood, and ischemic hemisphere af ter middle cerebral artery occlusion. RLIPoC was followed by subsequent alteration in metabo-lites, such as flavin adenine dinucleotide and nicotinamide adenine dinucleotide hydrate, both in RLIPoC-conducted local tissues and circulating blood. Furthermore, nicotinamide adenine dinucleotide hydrate can mimic RLIPoC in increasing Tregs. Conversely, the depletion of Tregs using depletion of Treg mice compromised the neuroprotective ef fects con-ferred by RLIPoC. CONCLUSIONS: RLIPoC protects against ischemic brain injury, at least in part by activating and maintaining the Tregs through the nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrate pathway.

Original languageEnglish (US)
Article numbere023077
JournalJournal of the American Heart Association
Issue number22
StatePublished - Nov 16 2021


  • Ischemic postconditioning
  • Ischemic stroke
  • Metabolism
  • Regulatory T cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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