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Fingolimod targets cerebral endothelial activation to block leukocyte recruitment in the central nervous system
Author(s) -
Zhao Yawei,
Shi Dongyan,
Cao Kelei,
Wu Fengjiao,
Zhu Xingxing,
Wen Shuang,
You Qiang,
Zhang Keqi,
Liu Lixin,
Zhou Hong
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3a0717-287r
Subject(s) - fingolimod , biology , pharmacology , chemokine , inflammation , s1pr1 , cell adhesion molecule , cxcl1 , immunology , sphingosine , phosphorylation , cancer research , microbiology and biotechnology , receptor , vascular endothelial growth factor a , multiple sclerosis , vascular endothelial growth factor , biochemistry , vegf receptors
Fingolimod (FTY720), an immunomodulator, is approved as an oral treatment for patients with relapsing forms of multiple sclerosis. Its effects are largely attributed to its mechanism of selectively retaining lymphocytes in the lymph nodes to reduce autoreactive T‐cell recruitment in the CNS. In this study, we investigated the therapeutic effect of FTY720 on an animal model of CNS inflammation induced by intracerebral ventricle LPS injection. We found that FTY720 treatment significantly prevented LPS‐induced neutrophil recruitment in the CNS by inhibiting leukocyte recruitment in cerebral microvessels. Furthermore, FTY720 also inhibited the expressions of adhesion molecules on the cerebral endothelium, but did not affect the expression levels of pro‐inflammatory cytokines (TNF‐α and IL‐6) and chemokines (CXCL1 and CXCL2) in the CNS parenchyma. The inhibition of endothelial activation was accompanied by reduced phosphorylation of signaling molecules, including serine/threonine‐specific protein kinase (Akt), STAT6, and nuclear factor‐κB. This FTY720‐attenuated inhibition of leukocyte recruitment and endothelial activation was reversed by blocking the functions of sphingosine kinase 2 or sphingosine‐1‐phosphate receptor 1. Our study demonstrated, for the first time, that FTY720 directly inhibits the phosphorylation of multiple signaling molecules in endothelial cells, thereby effectively blocking leukocyte recruitment in the CNS.