Andreone Benjamin J, Chow Brian Wai, Tata Aleksandra, Lacoste Baptiste, Ben-Zvi Ayal, Bullock Kevin, Deik Amy A, Ginty David D, Clish Clary B, Gu Chenghua
Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Neuron. 2017 May 3;94(3):581-594.e5. doi: 10.1016/j.neuron.2017.03.043. Epub 2017 Apr 13.
The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition specifically inhibits the caveolae-mediated transcytotic route readily used in the periphery. An unbiased lipidomic analysis reveals significant differences in endothelial cell lipid signatures from the CNS and periphery, which underlie a suppression of caveolae vesicle formation and trafficking in brain endothelial cells. Furthermore, lipids transported by Mfsd2a establish a unique lipid environment that inhibits caveolae vesicle formation in CNS endothelial cells to suppress transcytosis and ensure BBB integrity.
血脑屏障（BBB）提供了一个恒定的稳态脑环境，这对正常的神经功能至关重要。相对于外周内皮细胞，中枢神经系统内皮细胞有两个独特特性来维持血脑屏障的限制性，其中之一就是异常低的囊泡运输（转胞吞作用）速率。然而，目前尚不清楚这种低转胞吞作用速率是如何实现的。在这里，我们提出了一种机制，即中枢神经系统内皮细胞脂质组成的调节特异性地抑制了在外周很容易使用的小窝介导的转胞吞途径。一项无偏向性脂质组学分析揭示了中枢神经系统和外周内皮细胞脂质特征的显著差异，这是抑制脑内皮细胞中小窝囊泡形成和运输的基础。此外，由Mfsd2a转运的脂质建立了一个独特的脂质环境，该环境抑制中枢神经系统内皮细胞中小窝囊泡的形成，从而抑制转胞吞作用并确保血脑屏障的完整性。
