Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Ann Neurol. 2024 May;95(5):907-916. doi: 10.1002/ana.26877. Epub 2024 Feb 12.
Microglia/macrophages line the border of demyelinated lesions in both cerebral white matter and the cortex in the brains of multiple sclerosis patients. Microglia/macrophages associated with chronic white matter lesions are thought to be responsible for slow lesion expansion and disability progression in progressive multiple sclerosis, whereas those lining gray matter lesions are less studied. Profiling these microglia/macrophages could help to focus therapies on genes or pathways specific to lesion expansion and disease progression.
We compared the morphology and transcript profiles of microglia/macrophages associated with borders of white matter (WM line) and subpial gray matter lesions (GM line) using laser capture microscopy. We performed RNA sequencing on isolated cells followed by immunocytochemistry to determine the distribution of translational products of transcripts increased in WM line microglia.
Cells in the WM line appear activated, with shorter processes and larger cell bodies, whereas those in the GM line appear more homeostatic, with smaller cell bodies and multiple thin processes. Transcript profiling revealed 176 genes in WM lines and 111 genes in GM lines as differentially expressed. Transcripts associated with immune activation and iron homeostasis were increased in WM line microglia, whereas genes belonging to the canonical Wnt signaling pathway were increased in GM line microglia.
We propose that the mechanisms of demyelination and dynamics of lesion expansion are responsible for differential transcript expression in WM lines and GM lines, and posit that increased expression of the Fc epsilon receptor, spleen tyrosine kinase, and Bruton's tyrosine kinase, play a key role in regulating microglia/macrophage function at the border of chronic active white matter lesions. ANN NEUROL 2024;95:907-916.
多发性硬化症患者大脑的脑白质和皮质中，脱髓鞘病变的边界有小胶质细胞/巨噬细胞排列。人们认为与慢性白质病变相关的小胶质细胞/巨噬细胞负责多发性硬化症进展期的病变缓慢扩大和残疾进展，而与灰质病变相关的小胶质细胞/巨噬细胞则研究较少。对这些小胶质细胞/巨噬细胞进行分析可以帮助将治疗方法集中在与病变扩大和疾病进展相关的特定基因或途径上。
我们使用激光捕获显微镜比较了与脑白质（WM 线）和软脑膜下灰质病变（GM 线）边界相关的小胶质细胞/巨噬细胞的形态和转录谱。我们对分离的细胞进行 RNA 测序，然后进行免疫细胞化学染色，以确定 WM 线小胶质细胞中转录物翻译产物的分布。
WM 线的细胞表现出激活状态，其突起较短，细胞体较大，而 GM 线的细胞则表现出更稳态的状态，其细胞体较小，有多个薄突起。转录谱分析显示，WM 线有 176 个基因和 GM 线有 111 个基因表达差异。与免疫激活和铁稳态相关的转录物在 WM 线小胶质细胞中增加，而属于经典 Wnt 信号通路的基因在 GM 线小胶质细胞中增加。
我们提出脱髓鞘的机制和病变扩大的动态导致 WM 线和 GM 线的转录物表达不同，并假设 Fc 受体ε、脾酪氨酸激酶和布鲁顿酪氨酸激酶的表达增加在调节慢性活跃性白质病变边界的小胶质细胞/巨噬细胞功能方面发挥关键作用。神经病学年鉴 2024；95：907-916。
