Protein kinase Cβ as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis
Protein kinase Cβ as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis
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DOI：
10.1073/pnas.1302569110
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发表时间：
2013-09-03
影响因子：
11.1
通讯作者：
Platten, Michael
中科院分区：
文献类型：
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作者：
Lanz, Tobias V.;Becker, Simon;Platten, Michael
血脑屏障（BBB）的破坏是多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎急性炎性病变的标志。这种破坏可能先于并促进致脑性T细胞的浸润。导致血脑屏障破坏的信号事件尚不完全清楚，但似乎涉及紧密连接蛋白（如claudin）的失调。旨在稳定多发性硬化症血脑屏障的药物干预可能具有治疗潜力。在这里，我们展示了口服小分子LY-317615，一种合成的双吲哚马来酰亚胺和蛋白激酶C β的抑制剂，临床上正在研究用于治疗癌症，抑制激活的T细胞通过炎症内皮细胞屏障的转运，在那里它导致诱导紧密连接分子zona occluden -1， claudin 3和claudin 5以及其他关键参与跨内皮白细胞迁移的途径。用LY-317615治疗正在进行的实验性自身免疫性脑脊髓炎小鼠可改善炎症、脱髓鞘、轴突损伤和临床症状。虽然LY-317615剂量依赖性地抑制t细胞增殖和独立于抗原特异性的细胞因子产生，但其治疗效果在需要百日咳毒素的小鼠模型中被取消。这表明其抗炎和临床疗效主要是通过稳定血脑屏障，从而抑制脑源性T细胞的迁移而介导的。总的来说，我们的数据表明内皮蛋白激酶C β参与自身免疫性神经炎症中血脑屏障的稳定，并暗示血脑屏障靶向药物如LY-317615作为多发性硬化症的治疗方法具有治疗潜力。
Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase C beta, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase C beta in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS.