Theodor Kocher Institute, University of Bern, Bern, Switzerland.
Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
Eur J Immunol. 2022 Jan;52(1):161-177. doi: 10.1002/eji.202149238. Epub 2021 Sep 30.
The migration of CD4 effector/memory T cells across the blood-brain barrier (BBB) is a critical step in MS or its animal model, EAE. T-cell diapedesis across the BBB can occur paracellular, via the complex BBB tight junctions or transcellular via a pore through the brain endothelial cell body. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB, we here directly compared the transcriptome profile of pMBMECs favoring transcellular or paracellular T-cell diapedesis by RNA sequencing (RNA-seq). We identified the atypical chemokine receptor 1 (Ackr1) as one of the main candidate genes upregulated in pMBMECs favoring transcellular T-cell diapedesis. We confirmed upregulation of ACKR1 protein in pMBMECs promoting transcellular T-cell diapedesis and in venular endothelial cells in the CNS during EAE. Lack of endothelial ACKR1 reduced transcellular T-cell diapedesis across pMBMECs under physiological flow in vitro. Combining our previous observation that endothelial ACKR1 contributes to EAE pathogenesis by shuttling chemokines across the BBB, the present data support that ACKR1 mediated chemokine shuttling enhances transcellular T-cell diapedesis across the BBB during autoimmune neuroinflammation.
CD4 效应/记忆 T 细胞穿越血脑屏障 (BBB) 的迁移是 MS 或其动物模型 EAE 的关键步骤。T 细胞穿过 BBB 的穿越可以通过细胞旁途径发生，通过复杂的 BBB 紧密连接，或者通过穿过脑内皮细胞体的孔进行细胞内途径。我们利用原代小鼠脑微血管内皮细胞 (pMBMEC) 作为 BBB 的体外模型，通过 RNA 测序 (RNA-seq) 直接比较了有利于细胞内或细胞旁 T 细胞穿越的 pMBMEC 转录组谱。我们确定了非典型趋化因子受体 1 (Ackr1) 作为上调的主要候选基因之一，有利于细胞内 T 细胞穿越。我们证实了在 EAE 期间促进细胞内 T 细胞穿越的 pMBMECs 和中枢神经系统中的静脉内皮细胞中 ACKR1 蛋白的上调。内皮细胞 ACKR1 的缺失减少了体外生理流动下 pMBMECs 中细胞内 T 细胞的穿越。结合我们之前的观察结果，即内皮细胞 ACKR1 通过将趋化因子穿梭过 BBB 来促进 EAE 的发病机制，本数据支持 ACKR1 介导的趋化因子穿梭增强了自身免疫性神经炎症期间 BBB 内的细胞内 T 细胞穿越。
