| First Author | Zhong L | Year | 2019 |
| Journal | Glia | Volume | 67 |
| Issue | 3 | Pages | 498-511 |
| PubMed ID | 30484906 | Mgi Jnum | J:273247 |
| Mgi Id | MGI:6275733 | Doi | 10.1002/glia.23558 |
| Citation | Zhong L, et al. (2019) Lipid transporter Spns2 promotes microglia pro-inflammatory activation in response to amyloid-beta peptide. Glia 67(3):498-511 |
| abstractText | Accumulating 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 (Abeta42) 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 Abeta42-induced pro-inflammatory cytokine generation, suggesting that Spns2 promotes microglia pro-inflammatory activation through S1P-signaling. Spns2KO significantly reduced Abeta42-induced nuclear factor kappa B (NFkappaB) activity. S1P increased, while FTY720 dampened, Abeta42-induced NFkappaB activity, suggesting that Spns2 activates microglia inflammation through, at least partially, NFkappaB pathway. Spns2KO mouse brains showed significantly reduced Abeta42-induced microglia activation/accumulation and reduced levels of pro-inflammatory cytokines when compared with age-matched controls. More interestingly, Spns2KO ameliorated Abeta42-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. |
