Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes
| Autor: | Koki Kawakami, Junken Aoki, Andreane Cartier, Andrew Kuo, Wenji Piao, Yanbao Xiong, Keisuke Yanagida, Satoru Ishida, Timothy Hla, Jonathan S. Bromberg, Sylvain Galvani, Yu Hisano, Mari Kono, Asuka Inoue, Richard L. Proia, Yuki Ono, Kuniyuki Kano, Eric Engelbrecht |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
government.form_of_government Immunology Fluorescent Antibody Technique Real-Time Polymerase Chain Reaction Article Receptors G-Protein-Coupled Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Sphingosine CRISPR-Associated Protein 9 Lysophosphatidic acid Human Umbilical Vein Endothelial Cells Animals Humans Immunology and Allergy Receptors Lysophosphatidic Acid Receptor Sphingosine-1-Phosphate Receptors Research Articles S1PR1 G protein-coupled receptor Gene Editing LPAR1 Endothelial Cells Receptor Cross-Talk Cell biology Lymphatic Endothelium HEK293 Cells 030104 developmental biology Lymphatic system chemistry government Lymph Nodes CRISPR-Cas Systems Lysophospholipids 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Sphingosine 1-phosphate receptor-1 signaling via the Gi pathway is suppressed by lysophosphatidic acid receptor-1, which recruits β-arrestin to the heterotypic receptor complex. This mechanism occurs at sinus lining lymphatic endothelial cells of lymph nodes and modulates complex cell–cell junction structure. 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/β-arrestin coupling while suppressing Gαi signaling. S1pr1 and Lpar1-positive lymphatic endothelial cells (LECs) of lymph nodes exhibit constitutive S1PR1/β-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. Graphical Abstract |
| Databáze: | OpenAIRE |
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