Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.

Abstract

The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, which directly combat the infectious agent and recruit additional immune responses. This exuberant cytokine release paradoxically injures the host by triggering leakage from capillaries, tissue edema, organ failure, and shock. Current medical therapies target individual pathogens with antimicrobial agents or directly either blunt or boost the host's immune system. We explored a third approach: activating with the soluble ligand Slit an endothelium-specific, Robo4-dependent signaling pathway that strengthens the vascular barrier, diminishing deleterious aspects of the host's response to the pathogen-induced cytokine storm. This approach reduced vascular permeability in the lung and other organs and increased survival in animal models of bacterial endotoxin exposure, polymicrobial sepsis, and H5N1 influenza. Thus, enhancing the resilience of the host vascular system to the host's innate immune response may provide a therapeutic strategy for treating multiple infectious agents.

• Authors: Nyall R London, Weiquan Zhu, Fernando A Bozza, Matthew C P Smith, Daniel M Greif, Lise K Sorensen, Luming Chen, Yuuki Kaminoh, Aubrey C Chan, Samuel F Passi, Craig W Day, Dale L Barnard, Guy A Zimmerman, Mark A Krasnow, Dean Y Li
• Journal: Science translational medicine (Sci Transl Med) Vol. 2 Issue 23 Pg. 23ra19 (Mar 17 2010) ISSN: 1946-6242 [Electronic] United States
• PMID: 20375003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Catenins
• Cytokines
• Intercellular Signaling Peptides and Proteins
• Lipopolysaccharides
• Nerve Tissue Proteins
• ROBO4 protein, human
• Receptors, Cell Surface
• Receptors, Immunologic
• Robo4 protein, mouse
• Slit homolog 2 protein
• Delta Catenin

Topics

• Animals
• Cadherins (metabolism)
• Capillary Permeability (drug effects)
• Catenins (metabolism)
• Cell Line
• Cytokines (metabolism)
• Disease Models, Animal
• Endothelium, Vascular (drug effects, metabolism, pathology)
• Humans
• Influenza A Virus, H5N1 Subtype (drug effects, physiology)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Nerve Tissue Proteins (metabolism)
• Orthomyxoviridae Infections (complications, immunology, mortality, pathology)
• Protein Binding (drug effects)
• Protein Stability (drug effects)
• Protein Transport (drug effects)
• Receptors, Cell Surface (metabolism)
• Receptors, Immunologic (metabolism)
• Sepsis (complications, immunology, pathology)
• Signal Transduction (drug effects)
• Delta Catenin