S1 PR 3 is essential for phosphorylated fingolimod to protect astrocytes against oxygen‐glucose deprivation‐induced neuroinflammation via inhibiting TLR 2/4‐ NF κB signalling

Autor: Xiu-Lan Sun, Ji-Ye Huang, Lulu Cao, Ruo-Bing Guo, Juan Ji, Yin-Feng Dong, Ling Zhang, Jun Lu, Zheng-Zhen Chen, Jin Wu
Rok vydání: 2018
Předmět:
0301 basic medicine
Primary Cell Culture
Pharmacology
HMGB1
Neuroprotection
neuroinflammation
Phosphatidylinositol 3-Kinases
03 medical and health sciences
astrocyte
0302 clinical medicine
medicine
Animals
Humans
fingolimod
HMGB1 Protein
Phosphorylation
Receptor
Sphingosine-1-Phosphate Receptors
Neuroinflammation
PI3K/AKT/mTOR pathway
Inflammation
S1PR3
biology
sphingosine‐1‐phosphate receptor 3
Fingolimod Hydrochloride
Tumor Necrosis Factor-alpha
Chemistry
NF-kappa B
Original Articles
Cell Biology
Fingolimod
Toll-Like Receptor 2
Rats
Toll-Like Receptor 4
Disease Models
Animal
Receptors
Lysosphingolipid
030104 developmental biology
medicine.anatomical_structure
Astrocytes
Cultural Deprivation
biology.protein
Cytokines
Molecular Medicine
Original Article
Immunosuppressive Agents
030217 neurology & neurosurgery
Signal Transduction
medicine.drug
Astrocyte
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
1582-1838
DOI: 10.1111/jcmm.13596
Popis: Fingolimod (FTY720) 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 FTY720 (pFTY720), which was the principle active molecule in regulating astrocyte‐mediated inflammatory responses induced by oxygen‐glucose deprivation (OGD). Results demonstrated that pFTY720 could protect astrocytes against OGD‐induced injury and inflammatory responses. It significantly decreased pro‐inflammatory cytokines, including high mobility group box 1 (HMGB1) and tumour necrosis factor‐α (TNF‐α). Further, studies displayed that pFTY720 could prevent up‐regulation of Toll‐like receptor 2 (TLR2), phosphorylation of phosphoinositide 3‐kinase (PI3K) and nuclear translocation of nuclear factor kappa B (NFκB) p65 subunit caused by OGD. Sphingosine‐1‐phosphate receptor 3 (S1PR3) knockdown could reverse the above change. Moreover, administration of TLR2/4 blocker abolished the protective effects of pFTY720. Taken together, this study reveals that pFTY720 depends on S1PR3 to protect astrocytes against OGD‐induced neuroinflammation, due to inhibiting TLR2/4‐PI3K‐NFκB signalling pathway.
Databáze: OpenAIRE
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