Wang Yue, Jin Shijie, Sonobe Yoshifumi, Cheng Yi, Horiuchi Hiroshi, Parajuli Bijay, Kawanokuchi Jun, Mizuno Tetsuya, Takeuchi Hideyuki, Suzumura Akio
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
PLoS One. 2014 Oct 14;9(10):e110024. doi: 10.1371/journal.pone.0110024. eCollection 2014.
The blood-brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.
血脑屏障（BBB）由毛细血管内皮细胞、周细胞和血管周围星形胶质细胞组成，它们调节中枢神经系统的稳态。星形胶质细胞释放的音猬因子（SHH）在维持血脑屏障完整性方面发挥着重要作用。血脑屏障破坏和小胶质细胞激活是多种神经系统疾病（如多发性硬化症、帕金森病、肌萎缩侧索硬化症和阿尔茨海默病）的常见病理特征。白细胞介素-1β（IL-1β）是活化小胶质细胞释放的一种主要促炎细胞因子，可增加血脑屏障通透性。在此我们表明，IL-1β通过抑制星形胶质细胞SHH的产生，消除了星形胶质细胞对血脑屏障完整性的保护作用。星形胶质细胞条件培养基、SHH或SHH信号激动剂通过上调紧密连接蛋白增强了血脑屏障的完整性，而SHH信号抑制剂则消除了这些作用。此外，IL-1β增加了星形胶质细胞促炎趋化因子（如CCL2、CCL20和CXCL2）的产生，这些趋化因子诱导免疫细胞迁移并加剧血脑屏障破坏和神经炎症。我们的研究结果表明，星形胶质细胞SHH是一个潜在的治疗靶点，可用于恢复神经系统疾病患者受损的血脑屏障。
