Lipid transporter Spns2 promotes microglia pro‐inflammatory activation in response to amyloid‐beta peptide

GLIA - Tập 67 Số 3 - Trang 498-511 - 2019
Liansheng Zhong1,2, Xue Jiang2,3, Zhihui Zhu2, Haiyan Qin2, Michael B. Dinkins4, Ji‐Na Kong5, Silvia Leanhart4, Rebecca Wang6, Ahmed Elsherbini2, Erhard Bieberich4,2, Yujie Zhao1, Guanghu Wang2
1Department of Bioinformatics, Key Laboratory of Cell Biology of Ministry of Public Health, College of Life Sciences, China Medical University, Shenyang, China
2Department of Physiology, University of Kentucky, Lexington, Kentucky
3Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
4Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia
5Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
6Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland

Tóm tắt

AbstractAccumulating evidence indicates that neuroinflammation contributes to the pathogenesis and exacerbation of neurodegenerative disorders, such as Alzheimer's disease (AD). Sphingosine‐1‐phosphate (S1P) is a pleiotropic bioactive lipid that regulates many pathophysiological processes including inflammation. We present evidence here that the spinster homolog 2 (Spns2), a S1P transporter, promotes microglia pro‐inflammatory activation in vitro and in vivo. Spns2 knockout (Spns2KO) in primary cultured microglia resulted in significantly reduced levels of pro‐inflammatory cytokines induced by lipopolysaccharide (LPS) and amyloid‐beta peptide 1–42 oligomers (Aβ42) when compared with littermate controls. Fingolimod (FTY720), a S1P receptor 1 (S1PR1) functional antagonist and FDA approved drug for relapsing–remitting multiple sclerosis, partially blunted Aβ42‐induced pro‐inflammatory cytokine generation, suggesting that Spns2 promotes microglia pro‐inflammatory activation through S1P‐signaling. Spns2KO significantly reduced Aβ42‐induced nuclear factor kappa B (NFκB) activity. S1P increased, while FTY720 dampened, Aβ42‐induced NFκB activity, suggesting that Spns2 activates microglia inflammation through, at least partially, NFκB pathway. Spns2KO mouse brains showed significantly reduced Aβ42‐induced microglia activation/accumulation and reduced levels of pro‐inflammatory cytokines when compared with age‐matched controls. More interestingly, Spns2KO ameliorated Aβ42‐induced working memory deficit detected by Y‐Maze. In summary, these results suggest that Spns2 promotes pro‐inflammatory polarization of microglia and may play a crucial role in AD pathogenesis.

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GLIA

Tập 67 Số 3

498-511

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