sphingosine kinase 1 deficiency exacerbates lps-induced neuroinflammation鞘氨醇激酶1缺乏加剧lps-induced神经炎症.pdfVIP

Sphingosine Kinase 1 Deficiency Exacerbates LPS- Induced Neuroinflammation 1,2 1,2 1 2 1 Natalia M. Grin’kina , Eddy E. Karnabi , Dushyant Damania , Sunil Wadgaonkar , Ilham A. Muslimov , Raj Wadgaonkar1,2* 1 SUNY Downstate Medical Center, Brooklyn, New York, United States of America, 2 Department of Research and Development VA Medical Center, Brooklyn, New York, United States of America Abstract The pathogenesis of inflammation in the central nervous system (CNS), which contributes to numerous neurodegenerative diseases and results in encephalopathy and neuroinflammation, is poorly understood. Sphingolipid metabolism plays a crucial role in maintaining cellular processes in the CNS, and thus mediates the various pathological consequences of inflammation. For a better understanding of the role of sphingosine kinase activation during neuroinflammation, we developed a bacterial lipopolysaccharide (LPS)-induced brain injury model. The onset of the inflammatory response was observed beginning 4 hours after intracerebral injection of LPS into the lateral ventricles of the brain. A comparison of established neuroinflammatory parameters such as white matter rarefactions, development of cytotoxic edema, astrogliosis, loss of oligodendrocytes, and major cytokines levels in wild type and knockout mice suggested that the neuroinflammatory response in SphK12/ 2 mice was significantly upregulated. At 6 hours after intracerebroventricular injection of LPS in SphK12/ 2 mice, the immunoreactivity of the microglia markers and astrocyte marker glial fibrillary acidic protein (GFAP) were significantly increased, while the oligodendrocyte marker O4 was decr