New BBB Model Reveals That IL-6 Blockade Suppressed the BBB Disorder, Preventing Onset of NMOSD.
New BBB Model Reveals That IL-6 Blockade Suppressed the BBB Disorder, Preventing Onset of NMOSD.
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新的BBB模型显示，IL-6阻断抑制了BBB疾病，阻止了NMOSD的发作。
DOI：
10.1212/nxi.0000000000001076
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
Kanda T
中科院分区：
文献类型：
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作者：
Takeshita Y;Fujikawa S;Serizawa K;Fujisawa M;Matsuo K;Nemoto J;Shimizu F;Sano Y;Tomizawa-Shinohara H;Miyake S;Ransohoff RM;Kanda T
评价视神经肌病谱系障碍（NMOSD）的病理生理学和白细胞介素-6（IL-6）阻断剂（satralizumab）的治疗机制和水平，特别是在新的体外和离体人血脑屏障（BBB）模型和体内模型的血脑屏障（BBB）破坏方面。我们构建了新的静态体外和基于流动的离体模型，用于评估持续的屏障功能，白细胞移行，以及使用新建立的三重共培养系统的视神经肌球蛋白-免疫球蛋白G（NMO-IgG）和satralizumab在BBB中的脑内转移性，该系统专门用于密切模拟周细胞和星形胶质细胞终足的内皮细胞接触。在体内研究中，我们评估了小鼠抗IL-6受体抗体（MR 16 -1）对患有实验性自身免疫性脑脊髓炎（其中脊髓中IL-6浓度显著增加）的小鼠体内BBB破坏的影响。体外和离体实验表明，NMO-IgG增加了satralizumab和NMO-IgG的脑内转移性，satralizumab抑制了NMO-IgG诱导的T细胞迁移和屏障功能障碍。在体内研究中，IL-6信号传导的阻断抑制了T细胞向脊髓中的迁移，并防止了BBB通透性的增加。这些结果表明：（1）我们的体外和离体三重培养的BBB模型是评价屏障功能、白细胞迁移和脑内转移的理想模型：（2）NMO-IgG通过降低屏障功能和诱导星形胶质细胞分泌IL-6而增加NMO-IgG的脑内转移性，从而导致屏障功能障碍和破坏受控的细胞浸润;和（3）satralizumab，其可以在NMO-IgG存在下通过BBB，抑制BBB功能障碍和炎性细胞的浸润，导致预防NMOSD的发作。
To evaluate the pathophysiology of neuromyelitis optica spectrum disorder (NMOSD) and the therapeutic mechanism and levels of interleukin-6 (IL-6) blockade (satralizumab), especially with respect to blood-brain barrier (BBB) disruption with the new in vitro and ex vivo human BBB models and in vivo model. We constructed new static in vitro and flow-based ex vivo models for evaluating continued barrier function, leukocyte transmigration, and intracerebral transferability of neuromyelitis optica-immunoglobulin G (NMO-IgG) and satralizumab across the BBB using the newly established triple coculture system that are specialized to closely mimic endothelial cell contact of pericytes and endfeet of astrocytes. In the in vivo study, we assessed the effects of an anti–IL-6 receptor antibody for mice (MR16-1) on in vivo BBB disruption in mice with experimental autoimmune encephalomyelitis in which IL-6 concentration in the spinal cord dramatically increases. In vitro and ex vivo experiments demonstrated that NMO-IgG increased intracerebral transferability of satralizumab and NMO-IgG and that satralizumab suppressed the NMO-IgG–induced transmigration of T cells and barrier dysfunction. In the in vivo study, the blockade of IL-6 signaling suppressed the migration of T cells into the spinal cord and prevented the increased BBB permeability. These results suggest that (1) our triple-cultured in vitro and in ex vivo BBB models are ideal for evaluating barrier function, leukocyte transmigration, and intracerebral transferability; (2) NMO-IgG increased the intracerebral transferability of NMO-IgG via decreasing barrier function and induced secretion of IL-6 from astrocytes causing more dysfunction of the barrier and disrupting controlled cellular infiltration; and (3) satralizumab, which can pass through the BBB in the presence of NMO-IgG, suppresses the BBB dysfunction and the infiltration of inflammatory cells, leading to prevention of onset of NMOSD.