Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA.
Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA.
Neuron. 2024 Sep 4;112(17):2910-2921.e7. doi: 10.1016/j.neuron.2024.07.015. Epub 2024 Aug 13.
Microglia, the resident immune cells of the central nervous system, are intimately involved in the brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, less is known about microglia-endothelial cell interactions in the healthy brain. To investigate the role of microglia at a healthy BBB, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed the BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for the maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism. This effect was independent from microglial depletion, suggesting that PLX5622 has off-target effects on brain vasculature.
小胶质细胞是中枢神经系统的固有免疫细胞，它们密切参与大脑的基本过程，从发育过程中修剪神经突触到终生防止神经元过度活动。研究报告称，在疾病背景下，小胶质细胞在血脑屏障（BBB）中具有有益和有害的作用。然而，对于健康大脑中小胶质细胞-内皮细胞相互作用的了解较少。为了研究健康 BBB 中小胶质细胞的作用，我们使用集落刺激因子 1 受体（CSF1R）抑制剂 PLX5622 耗尽小胶质细胞，并分析了 BBB 的超微结构、通透性和转录组。有趣的是，我们发现，尽管小胶质细胞与内皮细胞直接接触，但在健康大脑中，它们对于 BBB 结构、功能或基因表达的维持并非必需。然而，我们发现 PLX5622 治疗会改变大脑内皮细胞的胆固醇代谢。这种作用与小胶质细胞耗竭无关，表明 PLX5622 对脑血管有非靶向作用。
