Research ArticleSepsis

Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza

Science Translational Medicine  17 Mar 2010:
Vol. 2, Issue 23, pp. 23ra19
DOI: 10.1126/scitranslmed.3000678

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Batten Down the Vascular Hatches Against the Storm

An organism under stress from a massive infection or burn reacts strongly to protect itself. Body-wide inflammation is triggered, but this response can have negative effects of its own. These can include a fast heart rate, abnormally high temperature, and a marked discharge of cytokines from the immune system, called a cytokine storm. Death often occurs in these patients, a result of the failure of multiple organs. In mice, London et al. now inhibit one of the consequences of a cytokine storm—leakage from the vasculature into the intercellular space—and can thereby prevent the lethal effects of bacterial and viral infection.

Cytokines released during a cytokine storm, including tumor necrosis factor and interleukin-1β, act on the cells of the vascular lining, weakening their junctions and allowing cells and fluid to leak in. Because the resulting edema is one cause of organ failure, London et al. have targeted this process. They show that an abbreviated version of a soluble ligand, called Slit, when added to cultured vascular endothelial cells, can strengthen the cell-cell contacts. Acting by increasing the amount of a cell adhesion protein, vascular endothelial cadherin, on the cell surface, Slit reduced the permeability of the endothelial cell layer. This was also true in whole animals; the authors injected mice with an immunogenic bacterial protein to simulate infection and then measured vascular leakage. They then tested whether Slit could help mice survive a severe infection. Whether infected with gut bacteria or H5N1 flu, treatment of the mice with the abbreviated Slit molecule improved their odds of surviving. Further, the ability of Slit to reduce vascular permeability in the face of a severe infection depended on another signaling molecule, the Robo4 receptor.

Sepsis and other illnesses in which a cytokine storm is triggered are difficult to treat effectively. The standard of care is rapid antibiotic administration and supportive treatment of patients, but this is too often ineffective. The approach described here by London et al. may yield another tool to fight the cytokine storm, a way to strengthen the ability of the body to withstand its own assault.


  • * These authors contributed equally to this work.

  • Citation: N. R. London, W. Zhu, F. A. Bozza, M. C. P. Smith, D. M. Greif, L. K. Sorensen, L. Chen, Y. Kaminoh, A. C. Chan, S. F. Passi, C. W. Day, D. L. Barnard, G. A. Zimmerman, M. A. Krasnow, D. Y. Li, Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza. Sci. Transl. Med. 2, 23ra19 (2010).

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