Pathogenic influenza viruses cause significant morbidity and mortality in humans. Influenza virus causes lung tissue damage by direct pulmonary epithelial injury and by its initiation of an aggressive innate inflammatory response. The sphingosine 1-phosphate (S1P) signaling system is well known for its role in modulation of immune cell trafficking. Using genetic and chemical tools to probe functions of the S1P1 receptor (S1P1-rec), we recently published that pulmonary endothelial cells (ECs) are central modulators of innate immune cell recruitment and cytokine responses early following influenza virus infection. Use of S1P1-rec agonist results in reduced influenza morbidity and mortality. While S1P1 receptor is found on ECs and lymphocytes within lung tissue, an S1P1-selective agonist suppressed cytokines and innate immune cell recruitment in wild-type and lymphocyte-deficient mice, clearly identifying pulmonary ECs as central regulators of cytokine storm. Now, we report a novel cytokine amplification loop requiring cellular cross-talk between pulmonary epithelial cells, ECs and plasmacytoid dendritic cells (pDCs). Cytokine amplification through this loop requires MyD88 and IRF7 signaling. Importantly, S1P1 signaling on ECs elicits a negative signal to pDCs leading to global suppression of cytokine amplification. These findings identify therapeutic control points to blunt pathology associated with influenza virus infection and further illuminate influenza pathogenesis.
- Copyright © 2013 by The American Association of Immunologists, Inc.