title: Sphingosine kinase 1 mediates neuroinflammation following cerebral ischemia.
abstract: Sphingosine kinases (Sphks) are the rate-limiting kinases in the generation of sphingosine-1-phosphate, which is a well-established intracellular pro-survival lipid mediator. Sphk2 has been reported to be protective following experimental stroke. We investigated the role of Sphk1 in cerebral ischemia using a mouse middle cerebral artery occlusion (MCAO) model and an in vitro glucose-oxygen deprivation (OGD) model. Sphk expression and activity were assessed in the ischemic brain with quantitative PCR (qPCR), Western blot, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Pharmacological and gene knockdown approaches were utilized to investigate the effects of Sphk1 on stroke outcomes. The expression of Sphk1 but not that of Sphk2 was rapidly induced in the cortical penumbra over 96h after MCAO, and the microglia were one of the major cellular sources of Sphk1 induction. Consistently, Sphk activity was enhanced in the cortical penumbra. In contrast to the protective role of Sphk2, pharmacological inhibition and cortical knockdown of Sphk1 reduced infarction at 24 and 96h after reperfusion. Additionally, the Sphk1 inhibitor improved the neurological deficits at 96h after reperfusion. Mechanistically, Sphk1 inhibition and knockdown significantly attenuated MCAO-induced expression of inflammatory mediators in the cortical penumbra. Moreover, using a conditioned medium transfer approach, we demonstrated that OGD-treated neurons induced the expression of Sphk1 and pro-inflammatory mediators in primary microglia, and the microglial induction of pro-inflammatory mediators by ischemic neurons was blunted by Sphk1 inhibition. Taken together, our results indicate that Sphk1 plays an essential role in mediating post-stroke neuroinflammation.
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China; Department of Skin & Cosmetic Research, Shanghai Skin Disease Hospital, Shanghai, China.
authors: Shuli
authors: S
authors: Zheng
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors: Shanwen
authors: S
authors: Wei
authors: College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors: Xiaoyu
authors: X
authors: Wang
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors: Yingxiu
authors: Y
authors: Xu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors: Yunqi
authors: Y
authors: Xiao
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors: Hui
authors: H
authors: Liu
authors: College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Electronic address: jialijia8@sina.com.
authors: Jia
authors: J
authors: Jia
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China. Electronic address: jiancheng8@hotmail.com.
authors: Jian
authors: J
authors: Cheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000188:drug therapy; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000737:chemistry; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D000099157:Sphingosine Kinase
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D005947:Glucose; D008840:Microfilament Proteins; D052247:Nitric Oxide Synthase Type II; D010751:Phosphopyruvate Hydratase; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C491049:Aif1 protein, mouse; C000603447:sphingosine kinase 2, mouse
keywords: Cerebral ischemia; Microglia; Neuroinflammation; Sphingosine kinase 1