Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, 210008, China.
Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China.
J Neuroinflammation. 2023 May 3;20(1):105. doi: 10.1186/s12974-023-02780-3.
Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism.
Bilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7-10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry.
CXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2).
Our study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia.
慢性脑缺血诱导的白质损伤（WMI）导致认知能力下降。星形胶质细胞和小胶质细胞在脱髓鞘和髓鞘再生过程中都起着至关重要的作用，但潜在的机制尚不清楚。本研究旨在探讨趋化因子 CXCL5 对慢性脑缺血后 WMI 和认知能力下降的影响及其潜在机制。
构建双侧颈总动脉狭窄（BCAS）模型模拟慢性脑缺血，使用 7-10 周龄雄性小鼠。构建星形胶质细胞条件性敲除（cKO）小鼠，并通过立体定位注射腺相关病毒（AAV）生成星形胶质细胞中过表达 Cxcl5 的小鼠。通过磁共振成像（MRI）、电子显微镜、组织学染色和 Western blot 评估 WMI。通过一系列神经行为测试检查认知功能。通过免疫荧光染色、Western blot 或流式细胞术分析少突胶质细胞前体细胞（OPC）的增殖和分化、小胶质细胞的吞噬作用。
BCAS 模型中胼胝体（CC）和血清中 CXCL5 显著升高，主要表达于星形胶质细胞中，Cxcl5 cKO 小鼠显示 WMI 和认知表现改善。重组 CXCL5（rCXCL5）在体外对 OPC 的增殖和分化没有直接作用。星形胶质细胞特异性 Cxcl5 过表达加重慢性脑缺血诱导的 WMI 和认知能力下降，而小胶质细胞耗竭则拮抗这种作用。重组 CXCL5 显著抑制小胶质细胞对髓鞘碎片的吞噬作用，该作用可被 CXCL5 受体 C-X-C 基序趋化因子受体 2（CXCR2）的抑制所挽救。
本研究揭示了星形胶质细胞源性 CXCL5 通过抑制小胶质细胞对髓鞘碎片的吞噬作用加重 WMI 和认知能力下降，提示 CXCL5-CXCR2 信号在慢性脑缺血中存在星形胶质细胞-小胶质细胞回路。
