Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
Department of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK.
FASEB J. 2020 Dec;34(12):16662-16675. doi: 10.1096/fj.202001539RR. Epub 2020 Oct 30.
We previously showed that calnexin (Canx)-deficient mice are desensitized to experimental autoimmune encephalomyelitis (EAE) induction, a model that is frequently used to study inflammatory demyelinating diseases, due to increased resistance of the blood-brain barrier to immune cell transmigration. We also discovered that Fabp5, an abundant cytoplasmic lipid-binding protein found in brain endothelial cells, makes protein-protein contact with the cytoplasmic C-tail domain of Canx. Remarkably, both Canx-deficient and Fabp5-deficient mice commonly manifest resistance to EAE induction. Here, we evaluated the importance of Fabp5/Canx interactions on EAE pathogenesis and on the patency of a model blood-brain barrier to T-cell transcellular migration. The results demonstrate that formation of a complex comprised of Fabp5 and the C-tail domain of Canx dictates the permeability of the model blood-brain barrier to immune cells and is also a prerequisite for EAE pathogenesis.
我们之前的研究表明，钙联蛋白（Canx）缺陷小鼠对实验性自身免疫性脑脊髓炎（EAE）的诱导具有脱敏作用，EAE 是一种常用于研究炎症性脱髓鞘疾病的模型，这是由于血脑屏障对免疫细胞迁移的抵抗力增强所致。我们还发现，Fabp5 是一种在脑内皮细胞中丰富的细胞质脂质结合蛋白，它与 Canx 的细胞质 C 尾域发生蛋白-蛋白接触。值得注意的是，Canx 缺陷和 Fabp5 缺陷的小鼠通常都表现出对 EAE 诱导的抵抗力。在这里，我们评估了 Fabp5/Canx 相互作用对 EAE 发病机制和模型血脑屏障对 T 细胞穿细胞迁移的通透性的重要性。结果表明，由 Fabp5 和 Canx 的 C 尾域组成的复合物的形成决定了模型血脑屏障对免疫细胞的通透性，也是 EAE 发病机制的前提条件。
