期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 5, 页码 2076-2086出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI71194
关键词
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资金
- Intramural Research Programs of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases
- Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]
- Lipidomics Core in the SC Lipidomics and Pathobiology COBRE [P20 RR017677]
Activation of the GPCR sphingosine-l-phosphate receptor 1 (S1P1) by sphingosine-l-phosphate (S1P) regulates key physiological processes. S1P1 activation also has been implicated in pathologic processes, including autoimm.unity and inflammation; however, the in vivo sites of S1P1 activation under normal and disease conditions are unclear. Here, we describe the development of a mouse model that allows in vivo evaluation of S1P1 activation. These mice, known as S1P1 GFP signaling mice, produce a S1P1 fusion protein containing a transcription factor linked by a protease cleavage site at the C terminus as well as a beta-arrestin/protease fusion protein. Activated S1P1 recruits the beta-arrestin/protease, resulting in the release of the transcription factor, which stimulates the expression of a GFP reporter gene. Under normal conditions, S1P1 was activated in endothelial cells of lymphoid tissues and in cells in the marginal zone of the spleen, while administration of an S1P1 agonist promoted S1P1 activation in endothelial cells and hepatocytes. In S1P1 GFP signaling mice, LPS-mediated systemic inflammation activated S1P1 in endothelial cells and hepatocytes via hematopoietically derived SW. These data demonstrate that S1P1 GFP signaling mice can be used to evaluate S1P1 activation and S1P1-active compounds in vivo. Furthermore, this strategy could be potentially applied to any GPCR to identify sites of receptor activation during normal physiology and disease.
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