Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke
Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke
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DOI：
10.1007/s00401-014-1355-2
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发表时间：
2015-02-01
影响因子：
12.7
通讯作者：
Gunzer, Matthias
中科院分区：
文献类型：
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作者：
Neumann, Jens;Riek-Burchardt, Monika;Gunzer, Matthias
缺血性卒中的神经元损伤因侵入外周免疫细胞而加重。中性粒细胞和T细胞的早期浸润影响中风的结局。然而，到目前为止，无论是中性粒细胞进入的时机还是细胞动力学，其对侵入脑区的后果，还是T细胞的相对重要性，都没有在活体环境中得到广泛研究。在这里，我们使用活体双光子显微镜记录诱导实验性中风后小鼠的中性粒细胞和脑内小胶质细胞。我们证明，中性粒细胞立即滚动，牢固地粘附，并在中风影响的脑区的内皮激活的网站transmigrated。随后的中性粒细胞浸润与局部血脑屏障破坏和梗死形成有关。脑内小胶质细胞识别内皮损伤和中性粒细胞浸润。它们以合作的方式形成细胞质突起，以物理方式屏蔽活化的内皮细胞并捕获浸润的中性粒细胞。有趣的是，非常晚期抗原-4的全身阻断立即且非常有效地抑制了内皮相互作用和中性粒细胞的脑进入。因此，这种治疗大大减少了缺血性组织损伤，并有效地保护小鼠免受中风相关的行为障碍。行为保护也同样很好地实现了抗体介导的骨髓细胞或特别是中性粒细胞的耗竭。相比之下，T细胞耗竭更有效地减少了梗死体积，而没有改善行为表现。因此，中性粒细胞侵入缺血性脑是快速、大量的，并且是功能损害的关键介质，而外周T细胞促进脑损伤。因此，急性消耗T细胞和抑制中性粒细胞的脑浸润可能是一种有效的早期中风治疗方法。
Neuronal injury from ischemic stroke is aggravated by invading peripheral immune cells. Early infiltrates of neutrophil granulocytes and T-cells influence the outcome of stroke. So far, however, neither the timing nor the cellular dynamics of neutrophil entry, its consequences for the invaded brain area, or the relative importance of T-cells has been extensively studied in an intravital setting. Here, we have used intravital two-photon microscopy to document neutrophils and brain-resident microglia in mice after induction of experimental stroke. We demonstrated that neutrophils immediately rolled, firmly adhered, and transmigrated at sites of endothelial activation in stroke-affected brain areas. The ensuing neutrophil invasion was associated with local blood-brain barrier breakdown and infarct formation. Brain-resident microglia recognized both endothelial damage and neutrophil invasion. In a cooperative manner, they formed cytoplasmic processes to physically shield activated endothelia and trap infiltrating neutrophils. Interestingly, the systemic blockade of very-late-antigen-4 immediately and very effectively inhibited the endothelial interaction and brain entry of neutrophils. This treatment thereby strongly reduced the ischemic tissue injury and effectively protected the mice from stroke-associated behavioral impairment. Behavioral preservation was also equally well achieved with the antibody-mediated depletion of myeloid cells or specifically neutrophils. In contrast, T-cell depletion more effectively reduced the infarct volume without improving the behavioral performance. Thus, neutrophil invasion of the ischemic brain is rapid, massive, and a key mediator of functional impairment, while peripheral T-cells promote brain damage. Acutely depleting T-cells and inhibiting brain infiltration of neutrophils might, therefore, be a powerful early stroke treatment.