Open AccessS1 PR 3 is essential for phosphorylated fingolimod to protect astrocytes against oxygen‐glucose deprivation‐induced neuroinflammation via inhibiting TLR 2/4‐ NF κB signalling
Author(s) -
Dong YinFeng,
Guo RuoBing,
Ji Juan,
Cao LuLu,
Zhang Ling,
Chen ZhengZhen,
Huang JiYe,
Wu Jin,
Lu Jun,
Sun XiuLan
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13596
Subject(s) - fingolimod , neuroinflammation , neuroprotection , pharmacology , chemistry , astrocyte , nf κb , microglia , tumor necrosis factor alpha , signal transduction , inflammation , medicine , immunology , biochemistry , multiple sclerosis , endocrinology , central nervous system
Fingolimod ( FTY 720) is used as an immunosuppressant for multiple sclerosis. Numerous studies indicated its neuroprotective effects in stroke. However, the mechanism remains to be elucidated. This study was intended to investigate the mechanisms of phosphorylated FTY 720 ( pFTY 720), which was the principle active molecule in regulating astrocyte‐mediated inflammatory responses induced by oxygen‐glucose deprivation ( OGD ). Results demonstrated that pFTY 720 could protect astrocytes against OGD ‐induced injury and inflammatory responses. It significantly decreased pro‐inflammatory cytokines, including high mobility group box 1 ( HMGB 1) and tumour necrosis factor‐α ( TNF ‐α). Further, studies displayed that pFTY 720 could prevent up‐regulation of Toll‐like receptor 2 ( TLR 2), phosphorylation of phosphoinositide 3‐kinase ( PI 3K) and nuclear translocation of nuclear factor kappa B ( NF κB) p65 subunit caused by OGD . Sphingosine‐1‐phosphate receptor 3 (S1 PR 3) knockdown could reverse the above change. Moreover, administration of TLR 2/4 blocker abolished the protective effects of pFTY 720. Taken together, this study reveals that pFTY 720 depends on S1 PR 3 to protect astrocytes against OGD ‐induced neuroinflammation, due to inhibiting TLR 2/4‐ PI 3K‐ NF κB signalling pathway.