These authors have contributed equally to this work and share the first authorship.
Department of Neurology, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China.
Neurol Res. 2023 Mar;45(3):248-259. doi: 10.1080/01616412.2022.2132456. Epub 2022 Oct 10.
White matter lesions (WML) are usually accompanied by cognitive decline, which consist of axonal loss and demyelination. CC chemokine ligand 21 (CCL21) and its receptor C-C chemokine receptor 7 (CCR7) belong to the chemokine family, which are involved in many diseases. However, their function in the central nervous system (CNS) is still unexplored. This study aimed to explore the role of CCL21/CCR7 axis in the pathological process of chronic ischemia-induced WML.
Bilateral common carotid artery stenosis (BCAS) was employed in C57BL/6 mice as the in vivo WML model. Microarray analysis was performed to detect the overall molecular changes induced in the endothelial cells by BCAS. Q-PCR, Western blotting, and immunofluorescence staining were performed to evaluate expression levels of the related molecules. The mice were injected with LV-CCL21-GFP virus in the corpus callosum to overexpress CCL21. WML degree was determined via MRI, and cognitive ability was assessed by Y-maze and novel object recognition tests. Myelin sheath integrity was evaluated via immunofluorescence staining.
CCL21 was significantly downregulated in endothelial cells after BCAS and CCL21 overexpression alleviated BCAS-induced cognitive deficits and demyelination. Furthermore, CCR7 was found to be mainly expressed in oligodendrocytes (OLs) after exposed to hypoxia and CCR7 silencing blocked the protective effects induced by CCL21 overexpression. Conclusions CCL21/CCR7 axis may play a key role in demyelination induced by BCAS. This might provide a novel therapeutic target for WML.
脑白质病变（WML）通常伴有认知能力下降，其主要由轴突丢失和脱髓鞘引起。趋化因子配体 21（CCL21）及其受体 C-C 趋化因子受体 7（CCR7）属于趋化因子家族，参与多种疾病的发生。然而，其在中枢神经系统（CNS）中的功能仍未被探索。本研究旨在探讨 CCL21/CCR7 轴在慢性缺血诱导 WML 病理过程中的作用。
采用双侧颈总动脉狭窄（BCAS）建立 C57BL/6 小鼠体内 WML 模型。通过微阵列分析检测 BCAS 诱导的内皮细胞整体分子变化。通过 Q-PCR、Western blot 和免疫荧光染色评估相关分子的表达水平。通过向胼胝体注射 LV-CCL21-GFP 病毒过表达 CCL21。通过 MRI 评估 WML 程度，通过 Y 迷宫和新物体识别测试评估认知能力。通过免疫荧光染色评估髓鞘完整性。
BCAS 后内皮细胞中 CCL21 表达明显下调，过表达 CCL21 可减轻 BCAS 诱导的认知功能障碍和脱髓鞘。此外，CCR7 主要在缺氧后表达于少突胶质细胞（OLs），CCR7 沉默阻断了 CCL21 过表达诱导的保护作用。结论：CCL21/CCR7 轴在 BCAS 诱导的脱髓鞘中可能发挥关键作用。这可能为 WML 提供新的治疗靶点。
