<br>在体外神经炎症中，ACKR1 有利于跨细胞而不是旁细胞 T 细胞渗出血脑屏障,European Journal of Immunology

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在体外神经炎症中，ACKR1 有利于跨细胞而不是旁细胞 T 细胞渗出血脑屏障
European Journal of Immunology ( IF 4.5 ) Pub Date : 2021-09-15 , DOI: 10.1002/eji.202149238
Luca Marchetti ₁ , David Francisco ₂ , Sasha Soldati ₁ , Neda Haghayegh Jahromi ₁ , Sara Barcos ₁ , Isabelle Gruber _{1,

3} , Javier R Pareja ₁ , Aude Thiriot _{4,

5} , Ulrich von Andrian _{4,

5} , Urban Deutsch ₁ , Ruth Lyck ₁ , Rémy Bruggmann ₂ , Britta Engelhardt ₁

Affiliation

CD4 ⁺效应/记忆 T 细胞穿过血脑屏障 (BBB) 的迁移是 MS 或其动物模型 EAE 的关键步骤。跨 BBB 的 T 细胞渗出可以通过复杂的 BBB 紧密连接发生在细胞旁，也可以通过穿过脑内皮细胞体的孔发生跨细胞。利用原代小鼠脑微血管内皮细胞 (pMBMEC) 作为 BBB 的体外模型，我们通过 RNA 测序 (RNA-seq) 直接比较了有利于跨细胞或旁细胞 T 细胞渗出的 pMBMEC 的转录组谱。我们确定非典型趋化因子受体 1 ( Ackr1 ) 是 pMBMEC 中上调的主要候选基因之一，有利于跨细胞 T 细胞渗出。我们证实了 EAE 期间 pMBMEC 中 ACKR1 蛋白的上调，促进跨细胞 T 细胞渗出，以及 CNS 中的小静脉内皮细胞中的 ACKR1 蛋白上调。体外生理流下，缺乏内皮 ACKR1 会减少跨 pMBMEC 的跨细胞 T 细胞渗出。结合我们之前的观察，即内皮 ACKR1 通过穿梭趋化因子穿过 BBB 来促进 EAE 发病机制，目前的数据支持 ACKR1 介导的趋化因子穿梭增强了自身免疫性神经炎症期间穿过 BBB 的跨细胞 T 细胞渗出。

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ACKR1 favors transcellular over paracellular T-cell diapedesis across the blood-brain barrier in neuroinflammation in vitro

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.

更新日期：2021-09-15

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