Journal of Inflammation Research (Jun 2025)
White Matter Anomaly Associated Cognitive Impairment During Systemic Inflammation Is Related to CX3CR1 Mediated Microglia-Node Interactions That Impacts the Conductive Function of Axons
Abstract
Xue Shi,1 Jingdong Zhang,1– 3 Huangying Zhao,3 Xinglong Yang,4 Feng Gao1 1Department 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; 2The 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; 3Division of Pharmaceutical Science, University of Cincinnati College of Pharmacy, Cincinnati, OH, 45267, USA; 4Core Facility of Research, The 5th Medical Center of PLA General Hospital, Beijing, 100071, People’s Republic of ChinaCorrespondence: Jingdong Zhang, The Key Laboratory of Molecular Biological Targeted Therapy of the Ministry of Education, Wuhan, 430022, People’s Republic of China, Email [email protected] Feng Gao, 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, Email [email protected]: 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.Methods: 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.Results: 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.Conclusion: 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 CX3CR1high circulating immune cells into the CC WM tract.Keywords: white matter tract, CX3CR1/CCR2 deficiency, microglia-node contact, axon compound action potential, cognitive performance, circulating immune cell infiltration
