小胶质细胞
CCL5
CX3CR1型
社会失败
趋化因子
神经科学
慢性应激
前额叶皮质
炎症
血脑屏障
趋化因子受体
生物
中枢神经系统
免疫学
免疫系统
认知
T细胞
白细胞介素2受体
作者
Hsiao‐Yun Lin,Flurin Cathomas,Long Li,Romain Durand-de Cuttoli,Christopher Guevara,Çiğdem Sevim Bayrak,Qian Wang,Swati Gupta,Kenny L. Chan,Yusuke Shimo,Lyonna F. Parise,Chongzhen Yuan,Antonio Aubry,Fiona Chen,Jean Wong,Carole Morel,George W. Huntley,Bin Zhang,Scott J. Russo,Jun Wang
标识
DOI:10.1101/2023.08.18.553789
摘要
Abstract Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.
科研通智能强力驱动
Strongly Powered by AbleSci AI