Abstract
BackgroundEvidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia. However, the spatio-temporal dynamics of brain-infiltrating lymphocytes during the late stage after cerebral ischemia remains unclear.MethodsC57BL/6 (B6) mice were subjected to sham, photothrombosis, or 60-min transient middle cerebral artery occlusion (MCAO) procedures. Infarct volume, neurodeficits, production of reactive oxygen species (ROS) and inflammatory factors, brain-infiltrating lymphocytes, and their activation as well as pro-inflammatory cytokine IFN-γ production were assessed. Brain-infiltrating lymphocytes were also measured in tissue sections from post-mortem patients after ischemic stroke by immunostaining.ResultsIn mice subjected to transient MCAO or photothrombotic stroke, we found that lymphocyte infiltration persists in the ischemic brain until at least day 14 after surgery, during which brain infarct volume significantly diminished. These brain-infiltrating lymphocytes express activation marker CD69 and produce proinflammatory cytokines such as IFN-γ, accompanied with a sustained increase of reactive oxygen species (ROS) and inflammatory cytokines release in the brain. In addition, brain-infiltrating lymphocytes were observed in post-mortem brain sections from patients during the late stage of ischemic stroke.ConclusionOur results demonstrate that brain-infiltration of lymphocytes persists after the acute stage of cerebral ischemia, facilitating future advanced studies to reveal the precise role of lymphocytes during late stage of stroke.
Highlights
Evidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia
Using a customized mouse cytokine ELISA panel, we assessed the expression of pro-inflammatory cytokines in the brain homogenates of photothrombosis and middle cerebral artery occlusion (MCAO) mice 14 days after surgery. We found that both photothrombosis and MCAO for 14 days showed upregulation of pro-inflammatory cytokines release including IL-1α, IL-1β, IFN-γ, IL-6, TNF-α, and CD69 compared with sham control
We found that the activating lymphocyte marker CD69 and IFN-γ were over-expressed in both stroke models compared with sham mice, but more in photothrombosis mice as compared to MCAO mice at 14 days after surgery
Summary
Evidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia. The spatio-temporal dynamics of brain-infiltrating lymphocytes during the late stage after cerebral ischemia remains unclear. Transient middle cerebral artery occlusion (MCAO) and photothrombotic ischemia are two commonly used murine models to study neuroinflammation in stroke. The post-ischemic inflammation and injury have been well documented during the early stage of ischemia in these two models, the features of cellular immune responses have not been adequately studied during the late stage. We determined the dynamics, activation, and cytokine production profiles of brain-infiltrating lymphocytes up to 14 days after photothrombotic and MCAO in mice during which brain infarct volume has significantly diminished, in conjunction with post-mortem human brain tissues from patients with ischemic stroke. Our results suggest that lymphocyte responses can persist in the brain at least for weeks after cerebral ischemia
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