title: CX3CL1/CX3CR1-mediated microglia activation plays a detrimental role in ischemic mice brain via p38MAPK/PKC pathway.
abstract: The exact roles of activated microglia and fractalkine (CX3CL1)/fractalkine receptor (CX3CR1) signaling are not fully understood in brain ischemic injury and the findings reported are controversial. Here, we investigated the effects of CX3CR1 siRNA on the expression of CX3CR1, p38 mitogen-activated protein kinase (p38MAPK), Protein Kinase C (PKC) and inflammatory cytokines, microglia activation, white matter lesions, and cognitive function in mice treated with bilateral common carotid artery stenosis (BCAS) in vivo as well as effects of exogenous CX3CL1, CX3CR1 siRNA, and SB2035080 on expression of inflammatory cytokines in BV2 microglia treated with oxygen-glucose deprivation (OGD) in vitro. We showed that CX3CR1 siRNA significantly inhibited the increased expression of CX3CR1, p38MAPK, PKC as well as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and also attenuated microglia activation, white matter lesions, and cognitive deficits induced by BCAS in mice brain. We also showed that exogenous CX3CL1 could induce a further enhancement in TNF-α and IL-1β expression, which could be suppressed by CX3CR1 siRNA or by the p38MAPK inhibitor in OGD-treated BV2 microglial cells in vitro. Our findings indicated that CX3CL1/CX3CR1-mediated microglial activation plays a detrimental role in ischemic brain via p38MAPK/PKC signaling and also suggested that CX3CL1/CX3CR1 axis might be a putative therapeutic target to disrupt the cascade of deleterious events that lead to brain ischemic injury.
authors.affiliation: Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Institute for Nautical Medicine, Nantong University, Nantong, China.|School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong, China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Wu
authors.affiliation: Department of Neurobiology, Institute for Nautical Medicine, Nantong University, Nantong, China.|Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Pu Dong, Shanghai, China.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Luo
authors.affiliation: Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Pu Dong, Shanghai, China.
authors.forename: Suna
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Qing-Wu Qian
authors.initials: QW
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Department of Neurobiology, Institute for Nautical Medicine, Nantong University, Nantong, China.|Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Pu Dong, Shanghai, China.
authors.forename: Zhong-Ming
authors.initials: ZM
authors.lastname: Qian
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology* / Q000523:psychology; D000073883:CX3C Chemokine Receptor 1; D016893:Carotid Stenosis / Q000473:pathology; D054428:Chemokine CX3CL1 / Q000235:genetics; D005947:Glucose / Q000172:deficiency; D002534:Hypoxia, Brain / Q000473:pathology / Q000523:psychology; D007276:Injections, Intraventricular; D053583:Interleukin-1beta / Q000378:metabolism; D008262:Macrophage Activation; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia; D011493:Protein Kinase C; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D066127:White Matter / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D053583:Interleukin-1beta; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose