Abstract
INTRODUCTION: Cerebral endothelial cells express large amounts of adhesion molecules, attracting peripheral immune cells to infiltrate into brain parenchyma. Regulatory T cell (Treg) was recently reported as a key cerebroprotective immunomodulator in ischemic stroke. HYPOTHESIS: We assessed the hypothesis that Treg transplantation could protect the ischemic brain from endothelial inflammation via cell-cell interaction. METHODS: Transient focal cerebral ischemia was induced in C57/BL6 mice by unilateral middle cerebral artery occlusion (MCAO) for 60 minutes. Tregs (2x10 6 /mouse) or same numbers of splenocytes were injected intravenously at 2 hours after MCAO. RESULTS: We found that Treg transplantation could inhibit ICAM-1 expression on endothelial cells in vitro by 3.86±0.04 folds (P<0.01) and also at 24 hours after ischemia in vivo, resulting in ameliorated blood brain barrier damage and reduced infiltration of peripheral immune cells, such as T cells, macrophage, and neutrophils. Further study showed that depletion of CCR5 on Tregs reduced the protective effect of Treg transplantation. Real-time PCR demonstrated 134±46 folds (P<0.05) increase of CCL3, the ligand of CCR5 in the ischemic brain at 24 hours after stroke. Immunofluorescence showed that CCL3, possibly released from activated microglia, was closely associated with inflamed endothelial cells. In vitro migration test further revealed that widetype Tregs migrated across the endothelial cell layer towards CCL3; CCR5 -/- Tregs, however, failed to migrate. CONCLUSIONS: In conclusion, Treg transplantation protected the ischemic brain against ICAM-1 experssion on endothelial cells and profoundly inhibited peripheral immune cell infiltration. A novel contributing mechanism was defined that CCR5 and CCL3 mediated recruitment of Tregs to inflamed endothelial cells and played an important role in the cell-cell interaction between Tregs and endothelial cells.
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