Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease

被引:86
|
作者
Karuppuchamy, T. [1 ,2 ]
Behrens, E-H [1 ,2 ]
Gonzalez-Cabrera, P. [3 ]
Sarkisyan, G. [3 ]
Gima, L. [1 ,2 ]
Boyer, J. D. [1 ,2 ]
Bamias, G. [4 ]
Jedlicka, P. [5 ]
Veny, M. [1 ,2 ]
Clark, D. [1 ,2 ]
Peach, R. [6 ]
Scott, F. [6 ]
Rosen, H. [3 ]
Rivera-Nieves, J. [1 ,2 ]
机构
[1] Univ Calif San Diego, Ctr Inflammatory Bowel Dis, Div Gastroenterol, La Jolla, CA 92093 USA
[2] VA San Diego Healthcare Syst, San Diego, CA 92161 USA
[3] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA
[4] Laikon Gen Hosp, Acad Dept Gastroenterol, Athens, Greece
[5] Univ Colorado Hlth Sci, Dept Pathol, Aurora, CO USA
[6] Receptos Inc, La Jolla, CA USA
基金
美国国家卫生研究院;
关键词
SPHINGOSINE 1-PHOSPHATE RECEPTOR; GENE-DEFICIENT MICE; CROHNS-DISEASE; MURINE ILEITIS; T-CELLS; MAINTENANCE THERAPY; MULTIPLE-SCLEROSIS; ULCERATIVE-COLITIS; FTY720; MIGRATION;
D O I
10.1038/mi.2016.35
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The sphingosine-1-phosphate receptor-1 (S1P(1)) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P(1) in intestine using S1P(1)-eGFP mice, the regulation of S1P(1) expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4(+) CD45RB(hi) cells, and by crossing a mouse with TNF-driven ileitis with S1P(1)-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P(1) expression. We found that not only T and B cells express S1P(1), but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P(1) expression, while the enzymes that control tissue S1P levels in mice and humans with inflammatory bowel disease (IBD) were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T-cell velocity and induced S1P(1) degradation and retention of Naive but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P(1) expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.
引用
收藏
页码:162 / 171
页数:10
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