Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection
Open accessAbstract
Cytokine storm during viral infection is a prospective predictor of morbidity and mortality, yet the cellular sources remain undefined. Here, using genetic and chemical tools to probe functions of the S1P(1) receptor, we elucidate cellular and signaling mechanisms that are important in initiating cytokine storm. Whereas S1P(1) receptor is expressed on endothelial cells and lymphocytes within lung tissue, S1P(1) agonism suppresses cytokines and innate immune cell recruitment in wild-type and lymphocyte-deficient mice, identifying endothelial cells as central regulators of cytokine storm. Furthermore, our data reveal immune cell infiltration and cytokine production as distinct events that are both orchestrated by endothelial cells. Moreover, we demonstrate that suppression of early innate immune responses through S1P(1) signaling results in reduced mortality during infection with a human pathogenic strain of influenza virus. Modulation of endothelium with a specific agonist suggests that diseases in which amplification of cytokine storm is a significant pathological component could be chemically tractable.
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S1P receptor 1 suppresses immune cell recruitment through downregulation of cytokine and chemokine production by respiratory endothelial cells in the presence of S1P1-selective agonists, CYM-5442 and RP-002, including production of IFN-alpha, CCL2, IL-6, TNF-alpha, and IFN-gamma.
“Sphingosine-1-phosphate (S1P) receptor 1 suppresses immune cell recruitment through downregulation of cytokine and chemokine production by respiratory endothelial cells in the presence of S1P 1 -selective agonists, CYM-5442 and RP-002, including production of IFN-␣, CCL2, IL-6, TNF-␣, and IFN-␥, (139).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [139]
Teijaro and colleagues demonstrated that blunted innate chemokine and cytokine responses mediated by S1P1-selective agonists protected mice from lethal infection with pandemic H1N1 influenza virus.
“Teijaro and colleagues (139) demonstrated that blunted innate chemokine and cytokine responses mediated by S1P 1 -selective agonists protected mice from lethal infection with pandemic H1N1 influenza virus.”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [139]
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Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.
de Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J. D., Chau, T. N. B., Hoang, D. M., Van Vinh Chau, N., Khanh, T. H., Dong, V. C., et al. (2006) · Nature Medicine · doi:10.1038/nm1477 · Cited by 1,858 · see citing works
Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis
Brinkmann, V., Billich, A., Baumruker, T., Heining, P., Schmouder, R., Francis, G., Aradhye, S., & Burtin, P. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3248 · Cited by 1,273 · see citing works
In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses
Itoh, Y., Shinya, K., Kiso, M., Watanabe, T., Sakoda, Y., Hatta, M., Muramoto, Y., Tamura, D., Sakai‐Tagawa, Y., Noda, T., et al. (2009) · Nature · doi:10.1038/nature08260 · Cited by 1,058 · see citing works
Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus.
Kobasa, D., Jones, S. M., Shinya, K., Kash, J. C., Copps, J., Ebihara, H., Hatta, Y., Hyun Kim, J., Halfmann, P., Hatta, M., et al. (2007) · Nature · doi:10.1038/nature05495 · Cited by 934 · see citing works
Type 1 Interferons and the Virus-Host Relationship: A Lesson in Detente
García‐Sastre, A., & Biron, C. A. (2006) · Science · doi:10.1126/science.1125676 · Cited by 880 · see citing works
Stacey, A., Norris, P. J., Li, Q., Haygreen, E. A., Taylor, E., Heitman, J. W., Lebedeva, M., deCamp, A. C., Li, D., Grove, D. I., et al. (2009) · Journal of Virology · doi:10.1128/jvi.01844-08 · Cited by 749 · see citing works
Hayden, F. G., Fritz, R., Lobo, M. C., Alvord, W. G., Strober, W., & Straus, S. E. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1355 · Cited by 680 · see citing works
The alliance of sphingosine-1-phosphate and its receptors in immunity
Rivera, J., Proia, R. L., & Olivera, A. (2008) · Nature Reviews Immunology · doi:10.1038/nri2400 · Cited by 616 · see citing works
Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus
Kobasa, D., Takada, A., Shinya, K., Hatta, M., Halfmann, P., Theriault, S., Suzuki, H., Nishimura, H., Mitamura, K., Sugaya, N., et al. (2004) · Nature · doi:10.1038/nature02951 · Cited by 455 · see citing works
A question of self‐preservation: immunopathology in influenza virus infection
Gruta, N. L. L., Kedzierska, K., Stambas, J., & Doherty, P. C. (2007) · Immunology and Cell Biology · doi:10.1038/sj.icb.7100026 · Cited by 454 · see citing works
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., et al. (2006) · Nature Chemical Biology · doi:10.1038/nchembio804 · Cited by 406 · see citing works
Self-citationSphingosine 1-Phosphate Receptor Signaling
Rosen, H., Gonzalez-Cabrera, P. J., Sanna, M. G., & Brown, S. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.072407.103733 · Cited by 404 · see citing works
Self-citationDawson, T. C., Beck, M. A., Kuziel, W. A., Henderson, F. W., & Maeda, N. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65068-7 · Cited by 379 · see citing works
Sánchez, T., Estrada-Hernandez, T., Paik, J., Wu, M.-T., Venkataraman, K., Brinkmann, V., Claffey, K. P., & Hla, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306896200 · Cited by 374 · see citing works
Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza
Bermejo-Martín, J. F., de Lejarazu, R. O., Pumarola, T., Rello, J., Almansa, R., Ramírez, P., Martín‐Loeches, I., Varillas‐Delgado, D., Gallegos, M. C., Arbeloa, C. S., et al. (2009) · Critical Care · doi:10.1186/cc8208 · Cited by 373 · see citing works
Rosen, H., & Gordon, S. (1987) · The Journal of Experimental Medicine · doi:10.1084/jem.166.6.1685 · Cited by 361 · see citing works
Self-citationSymptom pathogenesis during acute influenza: Interleukin‐6 and Other cytokine responses
Kaiser, L., Fritz, R. S., Straus, S. E., Gubareva, L. V., & Hayden, F. G. (2001) · Journal of Medical Virology · doi:10.1002/jmv.1045 · Cited by 347 · see citing works
Jo, E., Sanna, M., Gonzalez‐Cabrera, P. J., Thangada, S., Tigyi, G., Osborne, D. A., Hla, T., Parrill, A. L., & Rosen, H. (2005) · Chemistry & Biology · doi:10.1016/j.chembiol.2005.04.019 · Cited by 242 · see citing works
Self-citationCytokine Kinetics and Other Host Factors in Response to Pneumococcal Pulmonary Infection in Mice
Bergeron, Y., Ouellet, N., Deslauriers, A.-M., Simard, M., Olivier, M., & Bergeron, M. G. (1998) · Infection and Immunity · doi:10.1128/iai.66.3.912-922.1998 · Cited by 228 · see citing works
Cillóniz, C., Shinya, K., Peng, X., Korth, M. J., Proll, S. C., Aicher, L. D., Carter, V. S., Chang, J. H., Kobasa, D., Feldmann, F., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000604 · Cited by 210 · see citing works
Virulence determinants of pandemic influenza viruses
Tscherne, D. M., & García‐Sastre, A. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44947 · Cited by 203 · see citing works
The cytokine storm in multiple sclerosis
Link, H. (1998) · Multiple Sclerosis Journal · doi:10.1177/135245859800400104 · Cited by 155 · see citing works
Tipping the gatekeeper: S1P regulation of endothelial barrier function
Rosen, H., Sanna, M., Cahalan, S. M., & Gonzalez‐Cabrera, P. J. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.01.007 · Cited by 152 · see citing works
Self-citationInterferon and cytokine responses to SARS-coronavirus infection
Thiel, V., & Weber, F. (2008) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2008.01.001 · Cited by 149 · see citing works
Gonzalez‐Cabrera, P. J., Jo, E., Sanna, M., Brown, S. J., Leaf, N. B., Marsolais, D., Schaeffer, M., Chapman, J. V., Cameron, M. D., Guerrero, M., et al. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.049783 · Cited by 127 · see citing works
Self-citationMarsolais, D., Hahm, B., Walsh, K. B., Edelmann, K. H., McGavern, D., Hatta, Y., Kawaoka, Y., Rosen, H., & Oldstone, M. B. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812689106 · Cited by 122 · see citing works
Self-citationKawane, K., Tanaka, H., 北原, 雄., Shimaoka, S., & Nagata, S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010603107 · Cited by 108 · see citing works
Actions of a picomolar short-acting S1P1 agonist in S1P1-eGFP knock-in mice
Cahalan, S. M., Gonzalez‐Cabrera, P. J., Sarkisyan, G., Nguyen, N., Schaeffer, M., Huang, L., Yeager, A. R., Clemons, B., Scott, F. L., & Rosen, H. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.547 · Cited by 82 · see citing works
Self-citationThe cytokine storm in multiple sclerosis
Link, H. (1998) · Multiple Sclerosis Journal · doi:10.1191/135245898678909141 · Cited by 76 · see citing works
Hantavirus cardiopulmonary syndrome: immune response and pathogenesis
Borges, A. A., Campos, G. M., Moreli, M. L., et al. (2006) · Microbes and Infection · doi:10.1016/j.micinf.2006.04.019 · Cited by 73 · see citing works
Modulating tone: the overture of S1P receptor immunotherapeutics
Rosen, H., Gonzalez‐Cabrera, P. J., Marsolais, D., Cahalan, S. M., Don, A. S., & Sanna, M. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00645.x · Cited by 68 · see citing works
Self-citationMarsolais, D., Hahm, B., Edelmann, K. H., Walsh, K. B., Guerrero, M. A., Hatta, Y., Kawaoka, Y., Roberts, E., Oldstone, M. B. A., & Rosen, H. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.048769 · Cited by 65 · see citing works
Self-citationSphingosine 1-phosphate pathway therapeutics: a lipid ligand–receptor paradigm
Rosen, H., & Liao, J. (2003) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(03)00085-1 · Cited by 57 · see citing works
Self-citationInfluenza Virus Receptor Specificity
García‐Sastre, A. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100066 · Cited by 45 · see citing works
Influenza vaccination: lessons learned from the pandemic (H1N1) 2009 influenza outbreak
Openshaw, P., & Dunning, J. W. (2010) · Mucosal Immunology · doi:10.1038/mi.2010.34 · Cited by 9 · see citing works
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- Authors
- Teijaro, J. R., Walsh, K. B., Cahalan, S., Fremgen, D. M., Roberts, E., Scott, F., Martinborough, E., Peach, R., Oldstone, M. B. A., & Rosen, H.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Oldstone, Michael B.A.
- Rosen, Hugh
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 146
- Issue
- 6
- Pages
- 980-991
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3176439
- OpenAlex
- W1992974015
- Cited by
- 688
- References
- 35
- Citations by year
- 2026: 10 · 2025: 30 · 2024: 44 · 2023: 36 · 2022: 58 · 2021: 86 · 2020: 96 · 2019: 29 · 2018: 28 · 2017: 37 · 2016: 34 · 2015: 41 · 2014: 52 · 2013: 49 · 2012: 47
- FWCI
- 20.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Thailand Science Research and Innovation
- National Institutes of Health (5t32ns041219-10, MH084512, AI009484)
- U.S. Public Health Service (AI05509, MH084512, AI074564, AI009484)
- National Institute of Mental Health (U54MH084512, MH-084512)
- National Institute of Allergy and Infectious Diseases (AI-074564, T32AI007364, R01AI009484, AI007364, AI-009484, R01AI055509, U01AI074564, AI05509, T32AI007244, AI007244)
- National Institute of Neurological Disorders and Stroke (T32-NS041219, NS-041219)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- endothelial cells, cytokine storm, influenza, S1P1 receptor, sphingosine-1-phosphate signaling, innate immune response, immune cell recruitment, lung inflammation, lymphocytes, mortality
- MeSH terms
- Animals, Disease Models, Animal, Humans, Influenza, Human, Interferons, Lung, Lymphocytes, Mice, Inbred C57BL, Orthomyxoviridae Infections, Signal Transduction, Cytokines, Endothelial Cells, Receptors, Lysosphingolipid, Mice, Influenza A Virus, H1N1 Subtype
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