Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (Rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
J Neuroinflammation. 2023 Nov 13;20(1):262. doi: 10.1186/s12974-023-02947-y.
Ongoing neuroaxonal damage is a major contributor to disease progression and long-term disability in multiple sclerosis. However, spatio-temporal distribution and pathophysiological mechanisms of neuroaxonal damage during acute relapses and later chronic disease stages remain poorly understood.
Here, we applied immunohistochemistry, single-molecule array, spatial transcriptomics, and microglia/axon co-cultures to gain insight into spatio-temporal neuroaxonal damage in experimental autoimmune encephalomyelitis (EAE).
Association of spinal cord white matter lesions and blood-based neurofilament light (sNfL) levels revealed a distinct, stage-dependent anatomical pattern of neuroaxonal damage: in chronic EAE, sNfL levels were predominately associated with anterolateral lumbar lesions, whereas in early EAE sNfL showed no correlation with lesions in any anatomical location. Furthermore, neuroaxonal damage in late EAE was largely confined to white matter lesions but showed a widespread distribution in early EAE. Following this pattern of neuroaxonal damage, spatial transcriptomics revealed a widespread cyto- and chemokine response at early disease stages, whereas late EAE was characterized by a prominent glial cell accumulation in white matter lesions. These findings were corroborated by immunohistochemistry and microglia/axon co-cultures, which further revealed a strong association between CNS myeloid cell activation and neuroaxonal damage both in vivo and in vitro.
Our findings indicate that CNS myeloid cells may play a crucial role in driving neuroaxonal damage in EAE. Moreover, neuroaxonal damage can progress in a stage-dependent centripetal manner, transitioning from normal-appearing white matter to focal white matter lesions. These insights may contribute to a better understanding of neurodegeneration and elevated sNfL levels observed in multiple sclerosis patients at different disease stages.
神经轴突损伤是多发性硬化症疾病进展和长期残疾的主要原因。然而，急性发作和后期慢性疾病阶段神经轴突损伤的时空分布和病理生理机制仍知之甚少。
在这里，我们应用免疫组织化学、单分子阵列、空间转录组学和小胶质细胞/轴突共培养技术，深入了解实验性自身免疫性脑脊髓炎（EAE）中的时空神经轴突损伤。
脊髓白质病变与基于血液的神经丝轻链（sNfL）水平的相关性揭示了神经轴突损伤的一种独特的、与疾病阶段相关的解剖模式：在慢性 EAE 中，sNfL 水平主要与前外侧腰椎病变相关，而在早期 EAE 中，sNfL 与任何解剖部位的病变均无相关性。此外，晚期 EAE 中的神经轴突损伤主要局限于白质病变，但在早期 EAE 中呈广泛分布。根据这种神经轴突损伤模式，空间转录组学揭示了疾病早期广泛的细胞因子和趋化因子反应，而晚期 EAE 的特征是白质病变中明显的神经胶质细胞聚集。免疫组织化学和小胶质细胞/轴突共培养实验进一步证实了这一发现，这些实验进一步表明，中枢神经系统髓样细胞的激活与体内和体外的神经轴突损伤之间存在强烈的关联。
我们的研究结果表明，中枢神经系统髓样细胞可能在 EAE 中驱动神经轴突损伤中发挥关键作用。此外，神经轴突损伤可以以与疾病阶段相关的向心性方式进展，从正常外观的白质过渡到局灶性白质病变。这些见解可能有助于更好地理解多发性硬化症患者在不同疾病阶段观察到的神经退行性变和升高的 sNfL 水平。
