Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.

中文翻译：

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c-Kit+肥大细胞在 ALS 脊髓运动神经元血管生态位中的致病作用

运动神经元变性、神经胶质细胞反应性和中枢神经系统血管改变是肌萎缩侧索硬化症 (ALS) 的重要神经病理学特征。从血液中运输的免疫细胞也会渗透受影响的中枢神经系统实质并导致神经炎症。肥大细胞（MC）是造血来源的免疫细胞，其前体在迁移到组织中时分化。激活后，MC 会发生脱颗粒，从而增加血管通透性、协调神经炎症和调节神经免疫反应。然而，ALS 患者中枢神经系统中 MC 的患病率、病理意义和药理学仍然很大程度上未知。在尸检 ALS 脊髓中，我们首次发现 MC 与食糜酶、类胰蛋白酶和 Cox-2 一起表达 c-Kit，并与对照脊髓中稀有的 MC 相比，表现出颗粒状或脱颗粒形态。在ALS中，MCs主要存在于脊髓运动神经元胞体和附近微血管元件之间的微环境中，并且表现出显着的病理异常。同样，MC 在 ALS 小鼠模型的运动神经元血管生态位中积累，位于表达 c-Kit 配体干细胞因子 (SCF) 的星形胶质细胞和运动神经元附近，表明 MC 分化的 SCF/c-Kit 依赖性机制来自前体。从机制上讲，我们提供的证据表明，细胞培养物中完全分化的 MC 可以从小鼠 ALS 脊髓组织中产生，进一步支持 c-Kit+ MC 前体的存在。此外，静脉注射骨髓来源的 c-Kit+ MC 前体细胞会浸润 ALS 小鼠的脊髓，但在对照组中则不然，这与通过有缺陷的微脉管系统的异常运输一致。在 ALS 小鼠中，使用马赛替尼对 c-Kit 进行药理抑制可减少 MC 数量以及来自外周的 MC 前体的流入。我们的结果表明，ALS 运动神经元血管微环境中的 MC 触发了一种先前未知的致病机制，该机制可能是药理学目标。