期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 216, 期 7, 页码 1582-1598出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20181895
关键词
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资金
- National Institutes of Health [R35 HL135821, RO1AI062765, 1RO1AI14496]
- Fondation Leducq
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural program
- American Heart Association
- Japan Society for the Promotion of Science KAKENHI [17K08264]
- Japan Agency for Medical Research and Development [PRIME JP17gm5910013, LEAP JP17gm0010004]
- Japan Society for the Promotion of Science Overseas Research Fellowships
- Uehara Memorial Foundation
- ONO Pharmaceutical Corporation
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK056015, ZIADK056014] Funding Source: NIH RePORTER
Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) activate G protein-coupled receptors (GPCRs) to regulate biological processes. Using a genome-wide CRISPR/dCas9-based GPCR signaling screen, LPAR1 was identified as an inducer of S1PR1/beta-arrestin coupling while suppressing Gai signaling. S1pr1 and Lpar1-positive lymphatic endothelial cells (LECs) of lymph nodes exhibit constitutive S1PR1/beta-arrestin signaling, which was suppressed by LPAR1 antagonism. Pharmacological inhibition or genetic loss of function of Lpar1 reduced the frequency of punctate junctions at sinus-lining LECs. Ligand activation of transfected LPAR1 in endothelial cells remodeled junctions from continuous to punctate structures and increased transendothelial permeability. In addition, LPAR1 antagonism in mice increased lymph node retention of adoptively transferred lymphocytes. These data suggest that cross-talk between LPAR1 and S1PR1 promotes the porous junctional architecture of sinus-lining LECs, which enables efficient lymphocyte trafficking. Heterotypic inter-GPCR coupling may regulate complex cellular phenotypes in physiological milieu containing many GPCR ligands.
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