Overlapping roles of P-selectin and α4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis
Overlapping roles of P-selectin and α4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.169.2.1000
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发表时间：
2002-07-15
影响因子：
4.4
通讯作者：
Kubes, P
中科院分区：
文献类型：
--
作者：
Kerfoot, SM;Kubes, P
实验性自身免疫性脑脊髓炎（EAE）是由从循环募集到CNS的炎性细胞介导的。我们使用活体显微镜来研究这种招聘的机制。在健康对照小鼠中没有观察到白细胞滚动和非常少的粘附。相反，在EAE的身体症状发作之前，在脑毛细血管后微静脉中观察到滚动和粘附。滚动和粘连持续升高2周，症状发作后5周恢复至接近正常水平。与P-选择素在向CNS募集中的作用一致，在EAE小鼠的脑和脊髓中检测到P-选择素蛋白。在症状发作前表达最高，在接下来的2周内下降。α 4整合素的重要性随着时间的推移而增加，因为ami-alpha 4整合素在发病前2天、症状发作后5天和2周分别阻断了20%、50%和60%的白细胞滚动，在症状发作后5周阻断了85%的白细胞滚动。向α 4整联蛋白Ab处理的小鼠中添加抗P-选择蛋白阻断了每个时间点的所有剩余滚动。然而，有趣的是，α（4）整联蛋白介导的滚动似乎完全依赖于P-选择素，因为单独的抗P-选择素能够完全阻断所有白细胞滚动。在没有滚动的情况下（用P-选择素Ab），注意到粘附减少了70%。当用α（4）整联蛋白阻断Ab处理小鼠时，观察到非常相似的减少。总之，我们描述了EAE小鼠脑中白细胞运输的增加，P-选择素和α（4）整合素在介导白细胞-内皮细胞相互作用中具有重要的重叠作用。
Experimental autoimmune encephalomyelitis (EAE) is mediated by inflammatory cells recruited from the circulation to the CNS. We used intravital microscopy to investigate the mechanisms of this recruitment. No leukocyte rolling and very little adhesion was observed in healthy control mice. In contrast, both rolling and adhesion was observed in brain postcapillary venules before onset of physical symptoms of EAE. Rolling and adhesion remained elevated for 2 wk and returned to near normal levels by 5 wk postsymptom onset. Consistent with a role for P-selectin in recruitment to the CNS, P-selectin protein was detected in the brains and spinal cords of EAE mice. Expression was highest before symptom onset and decreased over the next 2 wk. The importance of alpha(4) integrin increased with time as ami-alpha(4) integrin blocked similar to20, 50, and 60% of leukocyte rolling 2 days before disease onset, 5 days and 2 wk postonset of symptoms, respectively, and 85% of rolling 5 wk postsymptoms. Addition of anti-P-selectin to a4 integrin Ab-treated mice blocked all remaining rolling at each time point. Interestingly, however, alpha(4) integrin-mediated rolling appeared to be entirely dependent on P-selectin as anti-P-selectin alone was able to completely block all leukocyte rolling. In the absence of rolling (with P-selectin Ab), a 70% reduction in adhesion was noted. A very similar reduction was seen when mice were treated with alpha(4) integrin-blocking Ab. In conclusion, we describe increased leukocyte trafficking in the brains of EAE mice with important overlapping roles for both P-selectin and alpha(4) integrin in mediating leukocyte-endothelial cell interactions.