Editors' ChoiceImmunology

Calming the Storm

Science Signaling  27 Sep 2011:
Vol. 4, Issue 192, pp. ec267
DOI: 10.1126/scisignal.4192ec267

Cells of the innate immune system are the first responders to infection by a pathogen; however, excessive activation of these cells (for example, during chronic influenza infection) results in the excessive production of inflammatory cytokines, the “cytokine storm,” which is associated with increased morbidity and mortality (see commentary by Iwasaki and Medzhitov). Noting that intratracheal administration of a nonselective agonist of sphingosine 1-phosphate (S1P) receptors (of which there are five) inhibits the cytokine storm in mice infected with influenza viruses, Teijaro et al. investigated the cellular sources of these cytokines. Treating mice that were infected with a mouse-adapted influenza virus or the human pathogenic isolate H1N1 with CYM-5442, a specific agonist of the S1P receptor S1P1, resulted in the production of smaller amounts of proinflammatory cytokines and chemokines than were produced by vehicle-treated infected mice and caused the reduced recruitment of innate immune cells to the lungs. Early administration of a different S1P1 agonist resulted in improved survival of mice infected with a lethal dose of H1N1 virus compared with that of vehicle-treated mice. Flow cytometric analysis showed that S1P1 was found on pulmonary endothelial cells and lymphocytes; however, treatment of lymphocyte-deficient mice with an S1P1 agonist still resulted in decreased cytokine production during infection, ruling out a role for lymphocyte-localized receptors in this process. Administration of recombinant chemokines to CYM-5442–treated mice resulted in the recruitment of specific innate immune cell types to the lungs but failed to substantially increase cytokine production. Together, these data implicate endothelial cells as central regulators of the cytokine storm and suggest that activation of S1P1 signaling in endothelial cells may provide a means to inhibit pathology during influenza infection.

J. R. Teijaro, K. B. Walsh, S. Cahalan, D. M. Fremgen, E. Roberts, F. Scott, E. Martinborough, R. Peach, M. B .A. Oldstone, H. Rosen, Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 146, 980–991 (2011). [PubMed]

A. Iwasaki, R. Medzhitov, A new shield for a cytokine storm. Cell 146, 861–862 (2011). [PubMed]