title: Sphk1 mediates neuroinflammation and neuronal injury via TRAF2/NF-κB pathways in activated microglia in cerebral ischemia reperfusion.
abstract: Sphingosine kinase 1 (Sphk1), a key enzyme responsible for phosphorylating sphingosine into sphingosine1-phosphate (S1P), plays an important role in mediating post-stroke neuroinflammation. However, the pathway and mechanism of the Sphk1-mediated inflammatory response remains unknown. In this study, we found that suppression of Sphk1 decreased IL17 production and relieved neuronal damage induced by microglia in cerebral ischemia reperfusion (IR) or in an in vitro oxygen-glucose deprivation reperfusion (OGDR) system. Inhibition of Sphk1 with an inhibitor or siRNA decreased tumor necrosis factor receptor-associated factor 2 (TRAF2) and nuclear factor-kappa B (NF-κB) sequentially in microglia in response to IR or OGDR. Moreover, we also found that after suppression of TRAF2 or NF-κB by siRNA in microglia, reductions in the downstream molecules NF-κB and IL-17 and in neuronal apoptosis were observed in response to OGDR. Taken together, we hypothesize that Sphk1, TRAF2 and NF-κB form an axis that leads to increased IL-17 and neuronal apoptosis. This axis may be a potential therapeutic target to control neuroinflammation in brain IR.
authors.affiliation: Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
authors.forename: Danying
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
authors.forename: Shi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Dai
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China. Electronic address: lvmanhua7266@163.com.
authors.forename: Manhua
authors.initials: M
authors.lastname: Lv
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D000432:Methanol; D017628:Microglia / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011759:Pyrrolidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015398:Signal Transduction / Q000502:physiology*; D013450:Sulfones / Q000627:therapeutic use; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D005947:Glucose; D020381:Interleukin-17; D000432:Methanol; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D011759:Pyrrolidines; D013450:Sulfones; D047992:TNF Receptor-Associated Factor 2; D000099157:Sphingosine Kinase; C573330:PF-543
keywords: Interleukin-17; Microglia; Neuroinflammation; Sphingosine kinase 1