全世界有数百万人患有多发性硬化症（MS）, a disease in which the immune system attacks cells in the central nervous system (CNS). MS causes unpredictable symptoms that can include tremors, weakness, vision problems, and fatigue.
治疗多发性硬化症的目的是通过控制免疫系统来保护神经元. This slows progression of the disease, but it also leaves patients more vulnerable to infection.
现在, a discovery from scientists at University of Utah Health suggests an alternative therapeutic strategy: restabilizing a natural barricade—the blood-CNS barrier—that breaks down in MS. 通常情况下，这一屏障使有害分子远离神经元.
Multiple sclerosis develops when wayward immune cells destroy the protective sheath that surrounds neurons. Its exact cause is unknown, but clearly inflammation helps drive the disease. 炎症会恶化, 在疾病早期, 保护性的血液-中枢神经系统屏障开始瓦解, allowing fluids and proteins in the blood to leak out of blood vessels and enter the brain and spinal cord.
“大发娱乐认为血液-中枢神经系统屏障的破坏正在造成一个真正的问题," says Shannon Odelberg博士， 内科学系研究副教授. "So, 如果你能稳定脉管系统，减少泄漏, 你可以减少那些造成损害的蛋白质, 你可以减少炎症反应."
在杂志上 神经元, Odelberg; 朱伟全（Wendy），博士， research assistant professor in the Department of Internal Medicine; and colleagues report that, 在多发性硬化症样的小鼠中, the blood-CNS barrier becomes leaky when the cells that line blood vessels’ interior walls transform and lose the ability to assemble themselves into a tight-knit layer. 他们发现他们可以通过逆转这种转变来恢复屏障. Once the barrier was repaired and inflammation-triggering molecules from the blood could no longer enter the CNS, 受损的神经元开始恢复, 动物的症状减轻了.
“大发娱乐认为血液-中枢神经系统屏障的破坏正在造成一个真正的问题."
Zhu says researchers are just beginning to recognize how changes in the blood vessels that supply the CNS contribute to the neurodegeneration characteristic of MS. But evidence is accumulating that breakdown of the blood-CNS barrier plays a role in a number of conditions. Deterioration of the barrier has also been observed in studies of Alzheimer’s disease, 帕金森病, 和亨廷顿舞蹈症. “大发娱乐认为血液-中枢神经系统屏障的破坏正在造成一个真正的问题,朱说.
朱和奥德伯格知道，当血液-中枢神经系统屏障破裂时, the cells that line blood vessels’ walls have often lost the physical junctions that usually link them tightly to their neighbors. 这可以防止有害分子在它们之间滑动, 就像红色漫游者停止前进的游戏中的手臂一样. 但当博士后研究员孙忠楼, 博士学位, 仔细观察了多发性硬化症小鼠的中枢神经系统, he discovered that the change to those cells went beyond the loss of these structural connections. 这些细胞似乎有了新的身份.
Sun discovered that some of the cells were no longer true endothelial cells, 排列在健康血管上的细胞类型. 而不是, 它们具有间充质细胞的特征, which do not produce the hinge-like proteins that link endothelial cells together. "Normally, they're really held tightly together to keep this fluid in," Odelberg explains. "But they lose those tight junctions when they convert to a mesenchymal cell type, allowing the fluid and the proteins to pass into the tissue where damage can occur."
通过进一步的实验, the team was able to trace how cellular signals that promote inflammation also trigger endothelial cells’ transition to be more like mesenchymal cells. 一旦研究人员识别出这些信号, they found that they could block the transition with compounds that targeted any of three different points along the signaling pathway. 即使在转变已经发生的时候, they could coax the mesenchymal cells in leaky blood vessels to revert to endothelial cells. 这样做可以稳定血液-中枢神经系统屏障. Damaged neurons began to recover, and the animals’ symptoms became less severe.
Further experiments are needed to better understand endothelial cells’ transition to mesenchymal cells and how to control it. 但考虑到血液-中枢神经系统屏障的关键作用, Zhu and Odelberg hope that reversing or preventing endothelial cells’ shift to mesenchymal cells could protect the CNS in people with MS—and possibly other neuroinflammatory diseases.
"Immunosuppressive drugs that are commonly used to treat MS can introduce some serious risks to the patient,朱说. "But the evidence suggests that the therapeutic strategy we explored in this study does not affect the immune system, thus providing a possible way to treat MS without causing the severe side effects associated with immunosuppression. 这是未来的潜在好处.
——作者：Jennifer Michalowski
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除了奥德伯格和朱, 共同作者：孙忠楼, 右边赵, 丹尼尔方, 查德威克戴维斯, 达拉斯史, Kachon Lei, 比安卡丰富, 雅各的冬天, 李郭, 丽丝索伦森, 罗伯特·普赖尔, 尼娜朱, 塞缪尔·卢, 劳拉·迪基, 丹尼尔多提, 柯克•托马斯, 艾莉Grossmann, and Robert Fujinami from University of Utah; Zongzhong Tong from ARUP Laboratories; Alan Mueller from Navigen, 公司.; Baowei Zhang from Anhui University; Thomas Lane from University of California, Irvine.
这项研究发表于 "Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling" in 神经元 8月11日, 2022, and was funded by the National Institutes of Health and the National Multiple Sclerosis Society.