MCP1-CCR2 与 TDP-43 病理学相关的 ALS 运动皮层中的神经炎症。
MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology.
机构信息
Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University Feinberg School of Medicine, Chicago, USA.
Les Turner ALS Center, Chicago, USA.
出版信息
J Neuroinflammation. 2019 Oct 30;16(1):196. doi: 10.1186/s12974-019-1589-y.
BACKGROUND
The involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies.
METHODS
We investigated the presence of astrogliosis and microgliosis in the motor cortex of ALS patients with TDP-43 pathology. prpTDP-43-UeGFP mice, corticospinal motor neuron (CSMN) reporter line with TDP-43 pathology, are utilized to reveal the timing and extent of neuroimmune interactions and the involvement of non-neuronal cells to neurodegeneration. Electron microscopy and immunolabeling techniques are used to mark and monitor cells of interest.
RESULTS
We detected both activated astrocytes and microglia, especially rod-like microglia, in the motor cortex of patients and TDP-43 mouse model. Besides, CCR2+ TMEM119- infiltrating monocytes were detected as they penetrate the brain parenchyma. Interestingly, Betz cells, which normally do not express MCP1, were marked with high levels of MCP1 expression when diseased.
CONCLUSIONS
There is an early contribution of a neuroinflammatory response for upper motor neuron (UMN) degeneration with respect to TDP-43 pathology, and MCP1-CCR2 signaling is important for the recognition of diseased upper motor neurons by infiltrating monocytes. The findings are conserved among species and are observed in both ALS and ALS-FTLD patients.
背景
非神经元细胞和固有免疫细胞的参与被认为是 ALS 的起始和进展的原因。TDP-43 病理学在广泛的 ALS 病例中被观察到，是最常见的共病之一。需要揭示 TDP-43 病理学 ALS 患者运动皮层中神经免疫轴的潜在参与。这些信息对于构建有效的治疗策略至关重要。
方法
我们研究了 TDP-43 病理学 ALS 患者运动皮层中星形胶质细胞和小胶质细胞的存在。利用携带 TDP-43 病理学的皮质脊髓运动神经元（CSMN）报告系 prpTDP-43-UeGFP 小鼠，揭示神经免疫相互作用的时间和程度以及非神经元细胞对神经退行性变的参与。电子显微镜和免疫标记技术用于标记和监测感兴趣的细胞。
结果
我们在患者和 TDP-43 小鼠模型的运动皮层中检测到了活化的星形胶质细胞和小胶质细胞，特别是杆状小胶质细胞。此外，还检测到穿透脑实质的 CCR2+TMEM119-浸润单核细胞。有趣的是，正常情况下不表达 MCP1 的贝茨细胞在患病时被标记为高水平表达 MCP1。
结论
TDP-43 病理学的上运动神经元（UMN）退变存在早期神经炎症反应的贡献，MCP1-CCR2 信号对浸润单核细胞识别病变的上运动神经元很重要。这些发现在物种间是保守的，在 ALS 和 ALS-FTLD 患者中都观察到。
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