Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection

By J. Teijaro, K. Walsh, Stuart M. Cahalan, D. Fremgen, E. Roberts, F. Scott, E. Martinborough, R. Peach, M. Oldstone, H. Rosen. Cell, 2011

675 citations recorded by the source corpus.

Summary 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 S1P1 receptor, we elucidate cellular and signaling mechanisms important in initiating cytokine storm. While S1P1 receptor is expressed on endothelial cells and lymphocytes within lung tissue, S1P1 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 both orchestrated by endothelial cells. Moreover, we demonstrate that suppression of early innate immune responses through S1P1 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 where amplification of cytokine storm is a significant pathological component could be chemically tractable.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/81c8d60b6692f0c7499e5fd40e3b3c7fba88ec84

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Citations in the corpus

Into the Eye of the Cytokine Storm (2012, background): “Teijaro and colleagues (139) demonstrated that blunted innate chemokine and cytokine responses mediated by S1P1-selective agonists protected mice from lethal infection with pandemic H1N1 influenza virus.”
The pathogenesis and treatment of the `Cytokine Storm' in COVID-19 (2020, background): “85 Agonists targeting S1P 1 inhibit excessive recruitment of inflammatory cells, inhibit proinflammatory cytokines and chemokines, and reduce the morbidity and mortality of IAV.”
The cytokine storm of severe influenza and development of immunomodulatory therapy (2015, background): “8 Particularly, in murine models infected with the 2009 H1N1 pandemic influenza, S1P1 receptor agonists alone reduced over 80% of deaths from lethal infection compared to 50% protection offered by the antiviral neuraminidase inhibitor, oseltamivir.”
Cross‐talk between Staphylococcus aureus leukocidins‐intoxicated macrophages and lung epithelial cells triggers chemokine secretion in an inflammasome‐dependent manner (2012, background): “, 2011) and endothelial cells (Teijaro et al., 2011), remain to be studied.”
Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology (2017, background): “agonism restrained excessive inflammatory cell recruitment, suppressed pro-inflammatory cytokines and chemokines, and reduced IAV induced morbidity and mortality [127, 128].”
Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination (2013, background): “Furthermore, suppression of this inflammatory response in infected mice ameliorates immunopathology and decreases mortality (6, 46).”