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J Exp Med. 2019 Jul 1;216(7):1582-1598. doi: 10.1084/jem.20181895. Epub 2019 May 30.

Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes.

Author information

1
Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA.
2
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
3
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
4
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
5
Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA timothy.hla@childrens.harvard.edu.
#
Contributed equally

Abstract

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.

PMID:
31147448
PMCID:
PMC6605750
[Available on 2020-01-01]
DOI:
10.1084/jem.20181895

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