Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection

• Published in: Cell 2011-09, Vol.146 (6), p.980-991
• Main Authors: Teijaro, John R., Walsh, Kevin B., Cahalan, Stuart, Fremgen, Daniel M., Roberts, Edward, Scott, Fiona, Martinborough, Esther, Peach, Robert, Oldstone, Michael B.A., Rosen, Hugh
• Format: Article
• Language: English
• Subjects: agonistic behavior; agonists; Animals; cell communication; cytokines; Cytokines - immunology; Disease Models, Animal; endothelial cells; Endothelial Cells - immunology; endothelium; human diseases; Humans; Influenza A Virus, H1N1 Subtype - physiology; Influenza virus; Influenza, Human - immunology; innate immunity; Interferons - immunology; Lung - cytology; Lung - immunology; Lung - virology; lungs; lymphocytes; Lymphocytes - immunology; Mice; Mice, Inbred C57BL; morbidity; mortality; Orthomyxoviridae; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - virology; Receptors, Lysosphingolipid - agonists; Signal Transduction; virulent strains
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.08.015

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. [Display omitted] ► S1P 1 signaling inhibits cytokine storms, potentially fatal immune responses ► S1P 1 signaling in the endothelium protects mice from pathogenic human influenza ► In cytokine storms, cytokine production and leukocyte recruitment are separate events ► S1P 1 signaling suppresses chemokine production by pulmonary endothelial cells The common flu virus can trigger potentially fatal immune reactions. In a surprising new role, endothelial cells of the lung express a potentially targetable receptor that suppresses this response.