Shi Xue, Zhang Jingdong, Zhao Huangying, Yang Xinglong, Gao Feng
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
The Key Laboratory of Molecular Biological Targeted Therapy of the Ministry of Education, and Hubei Key Laboratory of Biological Targeted Therapy, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
J Inflamm Res. 2025 Jun 26;18:8477-8492. doi: 10.2147/JIR.S513429. eCollection 2025.
The effects of CX3CR1 and CCR2 deficiency on cognition are related to microglia-neuron interactions and synaptic plasticity in the hippocampus. Contact between microglia and Ranvier's nodes has been identified in the brain white matter (WM). We propose that WM anomaly associated cognitive impairment during systemic inflammation is due to the alteration of microglia-node interactions, which impacts the conductive function of axons.
Novel object recognition and Y-maze tests were performed, and the corpus callosum (CC) axon compound action potential (CAP), microglia proportional area, density of microglia-node contact, and infiltrated circulating immune cells were examined in wild-type (WT), CX3CR1, and CCR2 knockout mice before and after systemic lipopolysaccharide (LPS) administration.
CX3CR1 deficiency significantly reduced rate of exploring new objects and new paths, decreased CC CAP and microglia-node contact compared with WT mice. CX3CR1 or CCR2 knockout diminished the microglial proportional area. Systemic LPS significantly increased microglial proportional area and immune cell infiltration but decreased time and rate of exploring new objects and new paths, declined CAP, and reduced microglia-node contact in CX3CR1 expressed mice. The absence of CX3CR1 in normal conditions deteriorated cognitive performance and CC WM tract conductive function and reduced microglia density and microglia-node contact chance. However, defects in cognitive performance and CC WM tract conductivity, and disruption of microglia-node contact by systemic LPS were protected by CX3CR1 knockout.
CX3CR1 is involved in modulating CC WM microglia-node contact, maintaining the CC WM tract conductive function, and improving cognitive performance. In the context of systemic LPS and associated neuroinflammation, CX3CR1 seems to dominate the disruption of microglia-node communication and CC WM tract conductive function, consequently causing cognitive problem. This may be achieved primarily through CX3CR1 mediated microglia activities and activation and subordinately via the infiltration of CX3CR1 circulating immune cells into the CC WM tract.
CX3CR1和CCR2缺乏对认知的影响与小胶质细胞-神经元相互作用及海马体中的突触可塑性有关。在脑白质（WM）中已发现小胶质细胞与郎飞结之间存在接触。我们提出，全身炎症期间与认知障碍相关的WM异常是由于小胶质细胞-郎飞结相互作用的改变，这会影响轴突的传导功能。
进行新物体识别和Y迷宫测试，并在野生型（WT）、CX3CR1和CCR2基因敲除小鼠全身注射脂多糖（LPS）前后，检测胼胝体（CC）轴突复合动作电位（CAP）、小胶质细胞比例面积、小胶质细胞-郎飞结接触密度以及浸润的循环免疫细胞。
与WT小鼠相比，CX3CR1缺乏显著降低了探索新物体和新路径的比率，降低了CC CAP以及小胶质细胞-郎飞结接触。CX3CR1或CCR2基因敲除减少了小胶质细胞比例面积。全身LPS显著增加了小胶质细胞比例面积和免疫细胞浸润，但减少了探索新物体和新路径的时间和比率，降低了CAP，并减少了CX3CR1表达小鼠中的小胶质细胞-郎飞结接触。正常条件下CX3CR1的缺失会恶化认知表现和CC WM束传导功能，并降低小胶质细胞密度和小胶质细胞-郎飞结接触机会。然而，CX3CR1基因敲除可保护认知表现和CC WM束传导性的缺陷以及全身LPS对小胶质细胞-郎飞结接触的破坏。
CX3CR1参与调节CC WM小胶质细胞-郎飞结接触，维持CC WM束传导功能，并改善认知表现。在全身LPS及相关神经炎症的背景下，CX3CR1似乎主导了小胶质细胞-郎飞结通讯的破坏和CC WM束传导功能，从而导致认知问题。这可能主要通过CX3CR1介导的小胶质细胞活动和激活来实现，其次是通过CX3CR1循环免疫细胞浸润到CC WM束中。
