A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis
A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis
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DOI：
10.1038/nm.2324
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发表时间：
2011-04-01
期刊：
影响因子：
82.9
通讯作者：
Kerschensteiner, Martin
中科院分区：
文献类型：
--
作者：
Nikic, Ivana;Merkler, Doron;Kerschensteiner, Martin
在多发性硬化症（一种常见的中枢神经系统炎性疾病）中，免疫介导的轴突损伤是永久性神经功能缺损的原因（1，2）。轴突损伤是如何开始的尚不清楚。在这里，我们使用在体内成像，以确定以前未描述的变异轴突损伤的多发性硬化症小鼠模型。这个过程，被称为“局灶性轴突变性”（FAD），其特征在于连续的阶段，开始于局灶性轴突损伤，并进展到轴突断裂。值得注意的是，大多数肿胀的轴突持续几天不变，有些会自发恢复。FAD的早期阶段可以在具有完整髓鞘的轴突中观察到。因此，与经典观点相反（2-6），脱髓鞘-多发性硬化的标志-不是轴突损伤的先决条件。相反，局灶性轴突内线粒体病变是损伤的最早超微结构体征，并且先于轴突形态学变化。分子影像学和药理学实验表明，巨噬细胞来源的活性氧和氮（ROS和RNS）可以触发线粒体病理，启动FAD。事实上，ROS和RNS的中和拯救了已经进入退行性过程的轴突。最后，在急性人类多发性硬化病变中可以检测到与FAD一致的轴突变化。总之，我们的数据表明，炎症性轴突损伤可能是自发可逆的，因此是一个潜在的治疗靶点。
In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits(1,2). How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view(2-6), demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.