Neutrophils Mediate Blood-Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases
Neutrophils Mediate Blood-Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases
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DOI：
10.4049/jimmunol.1400401
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发表时间：
2014-09-01
影响因子：
4.4
通讯作者：
Lacroix, Steve
中科院分区：
文献类型：
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作者：
Aube, Benoit;Levesque, Sebastien A.;Lacroix, Steve
血脑屏障和血脊髓屏障（分别为BBB和BSCB）的破坏和免疫细胞浸润是多发性硬化（MS）、其动物模型实验性自身免疫性脑脊髓炎（EAE）和视神经肌萎缩症（NMO）的早期病理生理学标志。然而，它们对疾病发生和发展的贡献仍不清楚。在这项研究中，我们在lys-eGFP-ki小鼠中诱导了EAE，并进行了单次非终末活体成像，以同时研究BSCB渗透性和GFP（+）骨髓细胞浸润的动力学。我们观察到BSCB的完整性在疾病发作的一天内丧失，这阻止了GFP（+）细胞向CNS的浸润，并持续了大约4天。中性粒细胞在EAE的临床前阶段占循环和CNS浸润髓样细胞的显著比例，并且它们的消耗延迟了EAE的发作并降低了EAE的严重程度，同时保持BSCB的完整性。我们还表明，从EAE小鼠的血液或骨髓中收集的中性粒细胞比在BBB细胞培养模型中的幼稚动物的中性粒细胞更有效地迁移。此外，使用活体视频显微镜，我们证明了IL-1 R 1型支配中性粒细胞与发炎的脊髓血管系统的牢固粘附。最后，从急性多发性硬化症患者和两个neuromyelocyte optica患者获得的死后CNS材料的免疫染色显示与BBB或BSCB渗漏区域相关的浸润性中性粒细胞的情况。总之，我们的数据提供的证据表明，中性粒细胞参与了EAE期间发生的初始事件，并且它们与BBB/BSCB的状态密切相关。
Disruption of the blood brain and blood spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP(+) myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP(+) cells into the CNS and lasted for similar to 4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.