Potential role of calcifying nanoparticles in the etiology of multiple sclerosis
Potential role of calcifying nanoparticles in the etiology of multiple sclerosis
复制标题
DOI：
10.1016/j.mehy.2019.05.005
复制
发表时间：
2019-07-01
影响因子：
4.7
通讯作者：
Demirdogen, Birsen Can
中科院分区：
文献类型：
--
作者：
Demirdogen, Birsen Can
纳米细菌或钙化纳米颗粒是80-500纳米大小的纳米生物体，物理上与碳酸盐磷灰石矿物形成有关。它们已被用于各种疾病，包括肾结石形成、阿尔茨海默病和动脉粥样硬化。纳米颗粒含有钙和磷灰石结合蛋白胎球蛋白-A，一种钙化抑制剂。然而，最近的证据表明，在过量的钙和磷灰石离子存在下，胎球蛋白-A可以通过离子沉淀形成成核种子或NIDI，成为更大的无定形纳米颗粒。胎球蛋白-A还可以作为MEPRIN的抑制剂，MEPRIN是一种与炎症和神经退行性疾病有关的金属蛋白酶。在炎症过程中，Meprin发挥调节单核细胞趋化蛋白1的趋化因子活性的作用，单核细胞趋化蛋白1与慢性炎症性疾病有关，包括动脉粥样硬化、肾脏炎症性疾病和多发性硬化症(MS)。此外，含有胎球蛋白-A的磷酸钙纳米晶对巨噬细胞具有促炎作用，并促进血管平滑肌细胞矿化，加剧炎症和钙化的恶性循环。因此，矿物质压力和炎症似乎是相互关联的。此外，胎球蛋白-A缺陷的小鼠表现出实验性自身免疫性脑脊髓炎的严重程度降低。因此，胎球蛋白-A在神经炎性反应中起着直接作用。事实上，脑脊液中胎球蛋白-A的水平已被定义为MS疾病活动的生物标志物。MS是一种病因不明的慢性、炎性、脱髓鞘和神经退行性疾病。最近的数据支持的多发性硬化症的“自内向外”模型认为，中枢神经系统中最初的轴突变性发生在脱髓鞘之前，然后刺激自身免疫攻击。最近的研究表明，通过轴突质膜的纳米级破裂从细胞外间隙进入细胞外的钙离子可以预测神经炎症中的轴突变性。钙是钙蛋白酶的激活剂，钙蛋白酶的功能是分解细胞骨架，导致神经退化。质膜的纳米断裂被认为发生在轴突损伤的早期阶段，特别是在无髓鞘的Ranvier结节。在此，我认为钙化纳米颗粒可能在MS的病因和/或病理生理学中起作用。导致神经变性的最初事件可能是由于纳米颗粒被认为很容易穿过血脑屏障。随后，纳米颗粒可能会在轴突膜上产生纳米孔，并通过形成NIDI进行钙化，增加神经元周围和内部的钙浓度，最终导致神经退化。纳米粒子可以自我复制；因此，它们可能是MS发生的感染性病原体。
Nanobacteria or calcifying nanoparticles are 80-500 nm sized nano-organisms that are physically associated with carbonate apatite mineral formations. They have been indicated in various diseases, including kidney stone formation, Alzheimer's disease, and atherosclerosis. Nanoparticles contain calcium and apatite-binding protein fetuin-A, a calcification inhibitor. However, recent evidence indicates that fetuin-A can form nucleation seeds or nidi that grow in size through ion sedimentation to become larger amorphous nanoparticles in the presence of excess calcium and apatite ions.Fetuin-A also functions as an inhibitor of meprin, a metalloproteinase implicated in inflammation and neurodegenerative diseases. During inflammation, meprin functions to regulate chemokine activity of monocyte chemotactic protein 1, which is associated with chronic inflammatory diseases, including atherosclerosis, renal inflammatory diseases, and multiple sclerosis (MS). In addition, calcium phosphate nanocrystals that contain fetuin-A are pro-inflammatory to macrophages and promote vascular smooth muscle cell mineralization, potentiating a vicious cycle of inflammation and calcification. Thus, mineral stress and inflammation appear to be associated with each other. Furthermore, fetuin-A deficient mice exhibited reduced experimental autoimmune encephalomyelitis severity. Thus, fetuin-A plays a direct role in the neuroinflammatory response. Indeed, the level of fetuin-A in cerebrospinal fluid has been defined as a biomarker of disease activity in MS.MS is a chronic, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) with an unknown etiology. The "inside-out" model of MS, supported by recent data, states that the initial axonal degeneration in the CNS occurs before demyelination, which then stimulates an auto-immune attack. It was shown very recently that influx of calcium from the extracellular space through nanoscale ruptures of the axonal plasma membrane predict axon degeneration in neuroinflammation. Calcium is an activator of calpains, proteases that function to break down the cytoskeleton, leading to neurodegeneration. Nanoruptures of the plasma membrane were suggested to occur at the early stages of axon damage, especially at nodes of Ranvier, which are devoid of myelin.Here, I propose that calcifying nanoparticles may have a role in the etiology and/or pathophysiology of MS. The initial event causing neurodegeneration may be due to the nanoparticles that have been suggested to easily cross the blood-brain barrier. Following this, the nanoparticles may create nanoruptures in the axonal membrane and also increase the calcium concentration around and within the neurons by forming nidi for calcification, eventually causing neurodegeneration. Nanoparticles can self-replicate; hence, they may represent an infectious causative agent for the development of MS.