Cited by 417Sphingolipid Metabolism and SignalingLymphatic System and DiseasesAdenosine and Purinergic Signaling

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Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo

Sanna, M Germana, Wang, Sheng-Kai, Gonzalez-Cabrera, Pedro J, Don, Anthony, Marsolais, David, Matheu, Melanie P, Wei, Sindy H, Parker, Ian, Jo, Euijung, Cheng, Wei-Chieh, Cahalan, Michael D, Wong, Chi-Huey, Rosen, Hugh·2006·Nature Chemical Biology

DOI 10.1038/nchembio804

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Abstract

Sphingosine 1-phosphate (S1P, 1) regulates vascular barrier and lymphoid development, as well as lymphocyte egress from lymphoid organs, by activating high-affinity S1P1 receptors. We used reversible chemical probes (i) to gain mechanistic insights into S1P systems organization not accessible through genetic manipulations and (ii) to investigate their potential for therapeutic modulation. Vascular (but not airway) administration of the preferred R enantiomer of an in vivo-active chiral S1P1 receptor antagonist induced loss of capillary integrity in mouse skin and lung. In contrast, the antagonist did not affect the number of constitutive blood lymphocytes. Instead, alteration of lymphocyte trafficking and phenotype required supraphysiological elevation of S1P1 tone and was reversed by the antagonist. In vivo two-photon imaging of lymph nodes confirmed requirements for obligate agonism, and the data were consistent with the presence of a stromal barrier mechanism for gating lymphocyte egress. Thus, chemical modulation reveals differences in S1P-S1P1 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention.

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RETRACTED: S1P 3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF
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Self-citation
Retracted
Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
Matloubian, M., Lo, C. G., Cinamon, G., Lesneski, M. J., Xu, Y., Brinkmann, V., Allende, M. L., Proia, R. L., & Cyster, J. G. (2004) · Nature · doi:10.1038/nature02284 · Cited by 2,581
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Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists
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Self-citation
CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs
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Edg-1, the G protein–coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation
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Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement
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Self-citation
Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate
Sanna, M., Liao, J., Jo, E., Alfonso, C., Ahn, M.-Y., Peterson, M. S., Webb, B., Lefebvre, S., Chun, J. J. M., Gray, N. S., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311743200 · Cited by 627
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Vascular reactions to histamine, histamine‐liberator and leukotaxine in the skin of guinea‐pigs
Miles, A. A., & Miles, E. M. (1952) · The Journal of Physiology · doi:10.1113/jphysiol.1952.sp004789 · Cited by 539

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BackgroundInfluential
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“In JURKAT cells, ChIP-seq data indicated that there are co-occupancies of TAL1 and RUNX1 at the 5 ’ position of S1PR3 locus (de ﬁ ned as RUNX1 binding region, RBR, 19.5 Kb from its transcriptional start site, TSS , Fig.”
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Background
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“While S1PR1 regulates immune cell function including lymphocyte egress from lymph nodes (Liu et al., 2000; Schwab et al., 2005; Sanna et al., 2006), S1PR2 is required for vestibular and auditory systems development (MacLennan et al., 2006; Ingham et al., 2016; Hofrichter et al., 2018), whereas…”
Background
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“W146: 5.09×10−4 ± 1.65×10−4 cm·s-1·cmH2O-1, p 0.05 and JTE013: 3.87×10−4 ± 0.96×10−4 cm·s-1·cmH2O-1, p 0.05 (Figure 3Aiii,Biii).”
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“The most interesting action of S1P1 agonists promising high clinical relevance was the ability to induce immunosuppression within a short time and at low concentrations [46].”
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“2005; Sanna et al.”
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“These have been reported to induce capillary leakage in the lung, kidney, skin and intestine in vivo [25, 56 , 57].”
Background
Optimising stem cell therapy for liver disease through modulation of sphingosine 1-phosphate signalling
King, A. (2014) · University of Birmingham Institutional Research Archive (University of Birmingham)
Sphingosine 1‐Phosphate (S1P) Signaling in Cardiovascular Physiology and Disease
Levkau, B. (2013) · Wiley eBooks · doi:10.1002/9781118531426.ch14
LYSOPHOSPHATIDIC ACID PRODUCTION AND SIGNALING IN PLATELETS
Fulkerson, Z. (2011) · UKnowledge (University of Kentucky)
Lysophospholipid Regulation of Lung Fibrosis
Shea, B. S., & Tager, A. M. (2013) · Wiley eBooks · doi:10.1002/9781118531426.ch27
Sphingosine 1‐Phosphate (S1P) Signaling and Lymphocyte Egress
Mendoza, A., Pitt, L. A., & Schwab, S. R. (2013) · doi:10.1002/9781118531426.ch22
S1P receptor agonists, a novel generation of immunosuppressants
Almagro, R. L., Tarrasón, G., & Godessart, N. (2010) · Cambridge University Press eBooks · doi:10.1017/cbo9780511760334.018
Longitudinal extension of primary afferents is regulated by sphingosine 1-phosphate receptors and tyrosine kinase receptor B in the embryonic spinal cord via a brain derived neurotrophic factor related mechanism
McNamara, M. A. (2015) · ScholarWorks -A service of University of Vermont Libraries (University of Vermont)
On the stimulatory effect of microglial cells on angiogenesis
Rymo, S. (2011) · Gothenburg University Publications Electronic Archive (Gothenburg University)
Genomics of Acute Lung Injury and Vascular Barrier Dysfunction
Machado, R. F., & Garcia, J. G. N. (2010) · Springer eBooks · doi:10.1007/978-0-387-87429-6_63
“In vivo administration of selective S1P1 competitive antagonists induces a dose-dependent disruption of barrier integrity in pulmonary endothelium [92, 93] , whereas S1P1 agonists, SEW2871 and FTY720, promote vascular endothelial barrier function [94] [95] [96] .”
Background
S1P Receptor Agonists
MILLER, C. A. (2012) · Royal Society of Chemistry eBooks · doi:10.1039/9781849735346-00417
The role of activated microglia in multiple sclerosis and clinically isolated syndromes: neuroimaging studies
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Review Article The role of sphingosine 1-phosphate in immunity and sepsis
Gräler, M. H. (2012)
Sphingosine 1-phosphate enhances excitability of sensory neurons through sphingosine 1-phosphate receptors 1 and/or 3
Li, C. (2014) · IUScholarWorks (Indiana University) · doi:10.7912/c2/2060
Effect of hypoxia on the cardiovascular sphingolipid system
Alganga, H. (2017) · Enlighten: Theses (The University of Glasgow)
Regulation of lysophospholipid signaling in development and cancer
Hurst, J. H. (2009)
Design, synthesis and biological evaluation of sphingosine kinase inhibitors for the treatment of prostate cancer
Tawati, S. M. (2018) · STAX · doi:10.48730/p5qa-vc44
Hyaluroan-regulated lymphatic permeability through S1P receptors is crucial for cancer metastasis
DuMan, H., Zhang, W., & Gao, C. Y. (2015)
Faculty Opinions recommendation of Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection.
Bradley, L. M., & Baaten, B. J. G. (2011) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.13353033.14724155
Peer Review #2 of "Regulation of S1P receptors and sphingosine kinases expression in acute pulmonary endothelial cell injury (v0.1)"
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Sphingosine 1-phosphate
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Peer Review #1 of "Regulation of S1P receptors and sphingosine kinases expression in acute pulmonary endothelial cell injury (v0.2)"
(2016) · PeerJ · doi:10.7287/peerj.2712v0.2/reviews/1
Peer Review #1 of "Regulation of S1P receptors and sphingosine kinases expression in acute pulmonary endothelial cell injury (v0.1)"
(2016) · PeerJ · doi:10.7287/peerj.2712v0.1/reviews/1
Peer Review #2 of "Regulation of S1P receptors and sphingosine kinases expression in acute pulmonary endothelial cell injury (v0.2)"
(2016) · PeerJ · doi:10.7287/peerj.2712v0.2/reviews/2
Selective S1PR1 activation improves brain infarction, neurological outcome, and cerebrovascular endothelial health following experimental ischemic injuryPreprint
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Pseudoirreversible inhibition elicits persistent efficacy of a sphigosine-1-phosphate receptor-1 antagonistPreprint
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Lysophospholipid (S1P) receptors in GtoPdb v.2023.1
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Endothelial Sphingosine-1-Phosphate Receptor (S1PR) 1, a Functional S1PR in the Human Cerebrovascular Endothelium, Limits Blood Brain Barrier Permeability and Neuronal Injury following Subarachnoid Hemorrhage in MicePreprint
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Structural basis of allosteric and bitopic ligands binding in sphingosine-1-phosphate receptors 2 and 3
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“…pocket shaped by N-terminus, helices II-III, ECL1, and an allosteric pocket formed by helices I, II, and VII, which is different from W146 (ML056), S1P and Siponimod in all solved S1P receptors (Chen et al., 2022; Liu et al., 2013; Hanson et al., 2012; Sanna et al., 2006; Yuan et al., 2021) (Figs.”
Sphingosine-1-phosphate effects on conventional outflow physiology
Sumida, G. M. (2010) · UA Campus Repository (The University of Arizona)
Pharmacological properties and clinical efficacy of sphingosine 1-phosphate (S1P) receptor modulator, Ozanimod (ZEPOSIA®)
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Targeting cholangiocyte sphingosine-1-phosphate (S1P) receptor 1 signaling alleviates cholestatic liver injury: Mechanistic insight into S1P/phosphorylated signal transducer and activator of transcription 3 axis
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Modulation de l’activité des corécepteurs CCR5 et CXCR4 du VIH 1 comme stratégie thérapeutique : étude des deux isoformes de CXCR4 et interaction de CCR5 avec le récepteur S1P1
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Implication du métabolisme de la sphingosine 1-phosphate dans les mécanismes biochimiques et cellulaires de la minéralisation dans la spondylarthrite ankylosante
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Role of the bone microenvironment in systemic breast cancer growth and metastasis
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Authors: Sanna, M. G., Wang, S.-K., Gonzalez-Cabrera, P. J., Don, A., Marsolais, D., Matheu, M. P., Wei, S. H., Parker, I., Jo, E., Cheng, W.-C., Cahalan, M. D., Wong, C.-H., & Rosen, H.
Affiliations: Scripps Research Institute (US)
University of California, Irvine (US)
Corresponding author: Wong, Chi-Huey
Rosen, Hugh
ORCID: Sanna, M Germana
Wang, Sheng-Kai
Don, Anthony
Marsolais, David
Wei, Sindy H
Parker, Ian
Jo, Euijung
Cheng, Wei-Chieh
Cahalan, Michael D
Wong, Chi-Huey
Rosen, Hugh
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2006-07-09
Volume: 2
Issue: 8
Pages: 434-441
ISSN: 1552-4450 (ISSN-L)
DOI: 10.1038/nchembio804
OpenAlex: W2151535044
Cited by: 406
References: 39
Citations by year: 2026: 3 · 2025: 8 · 2024: 11 · 2023: 10 · 2022: 8 · 2021: 7 · 2020: 18 · 2019: 22 · 2018: 6 · 2017: 20 · 2016: 21 · 2015: 22 · 2014: 21 · 2013: 44 · 2012: 35
FWCI: 12.52
Type: journal article
Language: en
Open access: closed
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
Funders: Kyorin Pharmaceutical
National Institutes of Health
U.S. Public Health Service (NIMH-074404)
National Institute of Mental Health
National Institute of General Medical Sciences (GM-48071, GM-41514, R01GM041514)
National Institute of Allergy and Infectious Diseases (AI-055509, R01AI055509)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Keywords: sphingosine-1-phosphate, S1P1 receptor, lymphocyte egress, lymphocyte migration, capillary leak syndrome, vascular barrier, lymphocyte sequestration, pulmonary edema, two-photon imaging
MeSH terms: Anilides, Animals, Capillary Permeability, Cells, Cultured, Disease Models, Animal, Evans Blue, Cricetinae, Humans, Lymph Nodes, Lymphocytes, Lysophospholipids, Mice, Inbred C57BL, Models, Biological, Phenotype, Pulmonary Edema, Sphingosine, Stereoisomerism, CHO Cells, Receptors, Lysosphingolipid, Mice, Organophosphonates

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Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo

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