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• W2014373825 abstract "Highly virulent influenza virus infection results in excessive cytokine production, recruitment of leukocytes, and immune-mediated pulmonary injury. Teijaro et al., 2011Teijaro J.R. Walsh K.B. Cahalan S. Fremgen D.M. Roberts E. Scott F. Martinborough E. Peach R. Oldstone M.B.A. Rosen H. Cell. 2011; 146 (this issue): 980-991Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar now demonstrate that sphingosine-1-phosphate receptor 1 ligands suppress all features of flu-inflicted pathological inflammation and place the endothelium at the center of this regulatory network. Highly virulent influenza virus infection results in excessive cytokine production, recruitment of leukocytes, and immune-mediated pulmonary injury. Teijaro et al., 2011Teijaro J.R. Walsh K.B. Cahalan S. Fremgen D.M. Roberts E. Scott F. Martinborough E. Peach R. Oldstone M.B.A. Rosen H. Cell. 2011; 146 (this issue): 980-991Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar now demonstrate that sphingosine-1-phosphate receptor 1 ligands suppress all features of flu-inflicted pathological inflammation and place the endothelium at the center of this regulatory network. Recognition and rapid clearance of pathogens by the innate immune system provide the first line of defense in metazoan organisms. However, excessive activation of the innate immune system in response to pathogens can lead to pathological inflammatory consequences. In the case of highly virulent 1918 and avian H5N1 influenza virus infections, early recruitment of inflammatory leukocytes to the lung, followed by excessive early cytokine responses (known as a cytokine storm), is considered to be the key contributor to morbidity and mortality of the infection (Tscherne and García-Sastre, 2011Tscherne D.M. García-Sastre A. J. Clin. Invest. 2011; 121: 6-13Crossref PubMed Scopus (131) Google Scholar). Likewise, the virulence of the pandemic 2009 H1N1 “swine flu” is associated with viral replication in the lower respiratory tract and more severe pulmonary damage compared to seasonal flu (Tscherne and García-Sastre, 2011Tscherne D.M. García-Sastre A. J. Clin. Invest. 2011; 121: 6-13Crossref PubMed Scopus (131) Google Scholar). However, the cell types that are responsible for the initiation and amplification of the cytokine storms that follow virulent influenza infection remain unclear. In this issue, Teijaro et al., 2011Teijaro J.R. Walsh K.B. Cahalan S. Fremgen D.M. Roberts E. Scott F. Martinborough E. Peach R. Oldstone M.B.A. Rosen H. Cell. 2011; 146 (this issue): 980-991Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar have uncovered an unexpected role of endothelial cells in coordinating the inflammatory sequelae via sphingosine-1-phosphate signaling. Sphingosine-1-phosphate is a metabolite of sphingolipid and is a ligand for a family of five G protein-coupled receptors, S1P1–5 (Rosen et al., 2009Rosen H. Gonzalez-Cabrera P.J. Sanna M.G. Brown S. Annu. Rev. Biochem. 2009; 78: 743-768Crossref PubMed Scopus (326) Google Scholar). Differential expression of these receptors enables control of angiogenesis, heart development, and immunity in a highly specific manner. The sphingosine analog FTY720, a well-known immunomodulator that has recently been approved for the treatment of multiple sclerosis, is phosphorylated in vivo by sphingosine kinase 2 to produce a ligand for the S1P receptors S1P1, 3–5. Its mode of action is through sequestration of lymphocytes in lymph nodes away from peripheral sites of inflammation. Prolonged exposure to FTY720 causes S1P1 endocytosis and degradation, impairing the ability of lymphocytes to respond to endogenous S1P to egress out of lymph nodes (Cyster, 2005Cyster J.G. Annu. Rev. Immunol. 2005; 23: 127-159Crossref PubMed Scopus (692) Google Scholar). The study by Teijaro et al., 2011Teijaro J.R. Walsh K.B. Cahalan S. Fremgen D.M. Roberts E. Scott F. Martinborough E. Peach R. Oldstone M.B.A. Rosen H. Cell. 2011; 146 (this issue): 980-991Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar followed up on previous findings by the same group that local intratracheal instillation of S1P ligands reduces cytokine responses following respiratory infections with a mouse-adapted influenza virus (Marsolais et al., 2008Marsolais D. Hahm B. Edelmann K.H. Walsh K.B. Guerrero M. Hatta Y. Kawaoka Y. Roberts E. Oldstone M.B. Rosen H. Mol. Pharmacol. 2008; 74: 896-903Crossref PubMed Scopus (54) Google Scholar, Marsolais et al., 2009Marsolais D. Hahm B. Walsh K.B. Edelmann K.H. McGavern D. Hatta Y. Kawaoka Y. Rosen H. Oldstone M.B. Proc. Natl. Acad. Sci. USA. 2009; 106: 1560-1565Crossref PubMed Scopus (102) Google Scholar) or human 2009 H1N1 influenza isolate (Walsh et al., 2011Walsh K.B. Teijaro J.R. Wilker P.R. Jatzek A. Fremgen D.M. Das S.C. Watanabe T. Hatta M. Shinya K. Suresh M. et al.Proc. Natl. Acad. Sci. USA. 2011; 108: 12018-12023Crossref PubMed Scopus (169) Google Scholar). These studies also revealed that the S1P1-specific agonists do not affect the generation of adaptive immune responses (CD8 T cells and neutralizing antibodies) and do not alter viral replication in vivo (Marsolais et al., 2008Marsolais D. Hahm B. Edelmann K.H. Walsh K.B. Guerrero M. Hatta Y. Kawaoka Y. Roberts E. Oldstone M.B. Rosen H. Mol. Pharmacol. 2008; 74: 896-903Crossref PubMed Scopus (54) Google Scholar). Using S1P1-specific agonists, the current study shows that stimulation of S1P1 alone recapitulates much of the suppressive phenotype of AAL-R, which is a broad-spectrum agonist of S1P receptors. Notably, intratracheal instillation of CYM-5442 (an S1P1 agonist) on hours 1, 13, 25, and 37 of influenza virus challenge significantly dampened type I interferon (IFN), cytokine, and chemokine release into the bronchoalveolar lavage (BAL) and resulted in a significant decrease in infiltration of monocytes, macrophages, neutrophils, and natural killer (NK) cells into the lung. In addition, oral administration of another S1P1 agonist, RP-002, at 1 and 25 hr after infection resulted in increased survival of mice challenged with 2009 H1N1 human isolate (Figure 1). To address the mechanism of action, the authors examined the expression of S1P1 using S1P1-eGFP knockin mice (Cahalan et al., 2011Cahalan S.M. Gonzalez-Cabrera P.J. Sarkisyan G. Nguyen N. Schaeffer M.T. Huang L. Yeager A. Clemons B. Scott F. Rosen H. Nat. Chem. Biol. 2011; 7: 254-256Crossref PubMed Scopus (54) Google Scholar). As reported previously, in addition to lymphocytes, a high level of S1P1 expression was found on lymphatic and vascular endothelial cells isolated from the lung (Cahalan et al., 2011Cahalan S.M. Gonzalez-Cabrera P.J. Sarkisyan G. Nguyen N. Schaeffer M.T. Huang L. Yeager A. Clemons B. Scott F. Rosen H. Nat. Chem. Biol. 2011; 7: 254-256Crossref PubMed Scopus (54) Google Scholar). However, influenza-induced cytokine responses and cellular recruitment to the lung were blocked by CYM-5442 in RAG2-deficient mice (devoid of T and B lymphocytes), suggesting that S1P1 stimulation dampens innate immune responses in a manner that is independent of its well-known function in lymphocyte sequestration. Next, the authors demonstrated that production of chemokines CCL2, CCL5, and CXCL10 from vascular and lymphatic endothelium following influenza infection was significantly reduced by CYM-5442 treatment in vivo. Intratracheal instillation of recombinant CCL2 restored monocyte, macrophage, and NK cell recruitment to the lung of mice treated with CYM-5442. Surprisingly, CCL2 was not sufficient to restore IFN or cytokine responses in the lung. Further, depletion of CD11b+ cells (including monocytes, macrophages, neutrophils, and NK cells) using antibody treatment only resulted in reduction in IFN-γ secretion but did not affect the levels of IFN-α, CCL2, IL-6, or TNF-α in the lung. These data indicate that inflammatory leukocyte recruitment is not sufficient for cytokine storm in the face of CYM-5442 treatment and is not required for the production of the majority of the cytokines in response to influenza infection. Finally, type I IFNs were placed upstream of the cytokine storm during influenza infection, as IFNαβR-deficient mice failed to secrete type I IFN, chemokines, or cytokines despite the normal recruitment of inflammatory leukocytes. The results of this study reveal an important role of S1P1 as a regulator of inflammation but also raise a host of questions. First, how does S1P1 agonism result in global suppression of cytokines? This may occur both at the cell-intrinsic level within the lung endothelial cells and at the cell-extrinsic level in the recruited leukocytes. S1P1 receptor is coupled to GαI, and receptor engagement triggers a multitude of downstream signaling pathways, including PI3K and Rac activation and promoting cell survival, motility, and barrier functions. S1P1 also activates the MAP kinase and phospholipase C pathways and intracellular mobilization of calcium signaling, resulting in cell proliferation and cytokine secretion (Rosen et al., 2009Rosen H. Gonzalez-Cabrera P.J. Sanna M.G. Brown S. Annu. Rev. Biochem. 2009; 78: 743-768Crossref PubMed Scopus (326) Google Scholar). However, it remains unclear whether any of these pathways directly inhibit cytokine and chemokine production by endothelial cells or, alternatively, whether S1P1-activated endothelial cells produce anti-inflammatory mediators. It is also possible that the anti-inflammatory effect of S1P1 engagement is an indirect consequence of its effect on vascular integrity. Second, why doesn't the endogenous S1P in the blood or lymph, which is maintained at high concentration (100–1,000 nM in blood and 30–300 nM in lymph), trigger a similar response in the endothelial cells? Unlike S1P, the synthetic agonists of S1P1, including CYM-5442, induce prolonged signaling, polyubiquitination of S1P1 followed by degradation in the lysosomes (Rosen et al., 2009Rosen H. Gonzalez-Cabrera P.J. Sanna M.G. Brown S. Annu. Rev. Biochem. 2009; 78: 743-768Crossref PubMed Scopus (326) Google Scholar). Whether endocytosis and degradation of S1P1 are requisite for immunosuppression by CYM-5442 and other S1P1 agonists remains to be determined. In this regard, it is interesting to speculate whether similar blockade of inflammation is caused by FTY720 and whether the clinical effects of this compound may, in part, depend on mechanisms that extend beyond lymphocyte sequestration. Following seasonal influenza infection, the virus replicates primarily in the lung epithelium, followed by infection of alveolar macrophages, dendritic cells, NK cells, and B cells (Manicassamy et al., 2010Manicassamy B. Manicassamy S. Belicha-Villanueva A. Pisanelli G. Pulendran B. García-Sastre A. Proc. Natl. Acad. Sci. USA. 2010; 107: 11531-11536Crossref PubMed Scopus (290) Google Scholar) (Figure 1). In contrast, H5N1 avian flu targets specifically endothelial cells for replication in birds (Feldmann et al., 2000Feldmann A. Schäfer M.K. Garten W. Klenk H.D. J. Virol. 2000; 74: 8018-8027Crossref PubMed Scopus (79) Google Scholar). Thus, it would be interesting to examine whether S1P1 agonists will be effective in the case of H5N1 influenza. Finally, the possible role of endothelial S1P1 in other conditions associated with excessive cytokine production would be an exciting question for future studies. Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus InfectionTeijaro et al.CellSeptember 16, 2011In BriefThe 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. Full-Text PDF Open Archive" @default.
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• W2014373825 title "A New Shield for a Cytokine Storm" @default.
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