Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
Institute of Neuroanatomy, RWTH Aachen University, Aachen, Germany.
Mol Neurobiol. 2018 Aug;55(8):6237-6249. doi: 10.1007/s12035-017-0838-2. Epub 2017 Dec 29.
Multiple sclerosis (MS) is a chronic degenerative disease of the central nervous system that is characterized by myelin abnormalities, oligodendrocyte pathology, and concomitant glia activation. The factors triggering gliosis and demyelination are currently not well characterized. New findings suggest an important role of the innate immune response in the initiation and progression of active demyelinating lesions. Especially during progressive disease, aberrant glia activation rather than the invasion of peripheral immune cells is accountable for progressive neuronal injury. The innate immune response can be induced by pathogen-associated or danger-associated molecular patterns, which are identified by pattern recognition receptors (PRRs), including the Toll-like receptors (TLRs). In this study, we used the cuprizone model in mice to investigate the expression of TLR2 during the course of cuprizone-induced demyelination. In addition, we used TLR2-deficient mice to analyze the functional role of TLR2 activation during cuprizone-induced demyelination and reactive gliosis. We show a significantly increased expression of TLR2 in the corpus callosum and hippocampus of cuprizone-intoxicated mice. The absence of receptor signaling in TLR2-deficient mice resulted in less severe reactive astrogliosis in the corpus callosum and cortex. In addition, microglia activation was ameliorated in the corpus callosum of TLR2-deficient mice, but augmented in the cortex compared to wild-type littermates. Extent of demyelination and loss of mature oligodendrocytes was comparable in both genotypes. These results suggest that the TLR2 orchestrates glia activation during gray and white matter demyelination in the presence of an intact blood-brain barrier. Future studies now have to address the underlying mechanisms of the region-specific TLR2-mediated glia activation.
多发性硬化症 (MS) 是一种中枢神经系统的慢性退行性疾病，其特征是髓鞘异常、少突胶质细胞病理学和伴随的神经胶质细胞激活。目前尚不清楚触发神经胶质细胞激活和脱髓鞘的因素。新的发现表明，固有免疫反应在活性脱髓鞘病变的发生和进展中起着重要作用。特别是在进行性疾病中，异常的神经胶质细胞激活而不是外周免疫细胞的入侵是进行性神经元损伤的原因。固有免疫反应可以被病原体相关或危险相关的分子模式所诱导，这些模式可以被模式识别受体 (PRRs) 识别，包括 Toll 样受体 (TLRs)。在这项研究中，我们使用杯状朊病毒模型在小鼠中研究了 TLR2 在杯状朊病毒诱导的脱髓鞘过程中的表达。此外，我们使用 TLR2 缺陷小鼠来分析 TLR2 激活在杯状朊病毒诱导的脱髓鞘和反应性神经胶质增生中的功能作用。我们发现，在杯状朊病毒中毒的小鼠的胼胝体和海马中，TLR2 的表达显著增加。在 TLR2 缺陷小鼠中缺乏受体信号导致胼胝体和皮质中的反应性星形胶质细胞增生减轻。此外，TLR2 缺陷小鼠的胼胝体中的小胶质细胞激活得到改善，但与野生型同窝仔相比，皮质中的小胶质细胞激活增强。脱髓鞘的程度和成熟少突胶质细胞的丢失在两种基因型中是可比的。这些结果表明，TLR2 在完整的血脑屏障存在的情况下，协调灰质和白质脱髓鞘过程中的神经胶质细胞激活。未来的研究现在必须解决 TLR2 介导的神经胶质细胞激活的区域特异性的潜在机制。
