Endothelial Cells Are Central Orchestrators of Cytokine Amplification

 during Influenza Virus Infection

John R. Teijaro, Kevin B. Walsh, Stuart Cahalan, Daniel M. Fremgen, Edward Roberts, Fiona Scott, Esther Martinborough, Robert Peach, Michael B.A. Oldstone, and Hugh Rosen

Cell 146, 980-991.

Speaker: Chun-Yung Lin (林峻暘)                               Time: 14:00~15:00, Apr. 11, 2012

Commentator: Dr. Li Jin Hsu (徐麗君老師)                Place: Room 601

Abstract:

　　        Cytokine storm is considered to be the key contributor to the morbidity and mortality of influenza infection. Antiviral drugs do not directly inhibit immune-mediated pulmonary injury that is a significant component of disease. The authors previously found that local intratracheal instillation of S1P ligands reduce cytokine responses following respiratory infections with influenza virus¹. However, the cell types that are responsible for the initiation of the cytokine storms remain unclear. To assess the contribution of S1P1 receptor signaling, infected mice were treated with the S1P1 receptor-specific agonist, CYM-5442 or RP-002. These S1P1 agonists suppressed cytokine and chemokine production and improved survival to lethal infection with H1N1 2009 swine flu. S1P1 receptor is expressed on pulmonary endothelium and lymphocytes, but not on pulmonary epithelial cells. CYM-5442 treatment of influenza virus-infected Rag^-/- lymphocyte-deficient mice or CCR2-deficient mice inhibited the innate inflammatory response. Administration of rmCCL2 to infected mice treated with CYM-5442 restored macrophage/monocyte and NK cell numbers in the lung, but still reduced cytokines and chemokines. Treatment with anti-CD11b, which inhibits the recruitment of macrophages/monocytes, neutrophils, and NK cells into the lung, also showed no reduction in levels of proinflammatory cytokines/chemokines. It excluded lymphocytes and macrophage/monocyte as key regulators of influenza virus-induced cytokine storm. It also demonstrated that inflammatory cell infiltration into the lung was not required for cytokine and chemokine production. Blunting IFN-a production may be a mechanism by which CYM-5442 inhibits cytokine storm. IFNa/b receptor knockout mice reduced levels of cytokine and chemokine production. Collectively, these data  demonstrate that S1P1 receptor agonism of endothelial cells inhibits IFN-a production and results in dampening global proinflammatory cytokine responses. The possible role of endothelial S1P1 in other conditions associated with excessive cytokine production would be an question for future studies.

Reference:

1          Marsolais, D. et al. A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection. Proc Natl Acad Sci U S A 106, 1560-1565, doi:10.1073/pnas.0812689106 (2009).