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

Nyall 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

Research output: Contribution to journalArticle

Abstract

The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, 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.

Original languageEnglish (US)
JournalScience translational medicine
Volume2
Issue number23
DOIs
StatePublished - Jun 7 2010
Externally publishedYes

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Human Influenza
Sepsis
Cytokines
Blood Vessels
Immune System
Tissue Survival
Capillary Permeability
Anti-Infective Agents
Interleukin-1
Innate Immunity
Endotoxins
Endothelium
Shock
Edema
Animal Models
Tumor Necrosis Factor-alpha
Ligands
Lung
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza. / London, Nyall; Zhu, Weiquan; Bozza, Fernando A.; Smith, Matthew C.P.; Greif, Daniel M.; Sorensen, Lise K.; Chen, Luming; Kaminoh, Yuuki; Chan, Aubrey C.; Passi, Samuel F.; Day, Craig W.; Barnard, Dale L.; Zimmerman, Guy A.; Krasnow, Mark A.; Li, Dean Y.

In: Science translational medicine, Vol. 2, No. 23, 07.06.2010.

Research output: Contribution to journalArticle

London, N, Zhu, W, Bozza, FA, Smith, MCP, Greif, DM, Sorensen, LK, Chen, L, Kaminoh, Y, Chan, AC, Passi, SF, Day, CW, Barnard, DL, Zimmerman, GA, Krasnow, MA & Li, DY 2010, 'Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza', Science translational medicine, vol. 2, no. 23. https://doi.org/10.1126/scitranslmed.3000678
London, Nyall ; Zhu, Weiquan ; Bozza, Fernando A. ; Smith, Matthew C.P. ; Greif, Daniel M. ; Sorensen, Lise K. ; Chen, Luming ; Kaminoh, Yuuki ; Chan, Aubrey C. ; Passi, Samuel F. ; Day, Craig W. ; Barnard, Dale L. ; Zimmerman, Guy A. ; Krasnow, Mark A. ; Li, Dean Y. / Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza. In: Science translational medicine. 2010 ; Vol. 2, No. 23.
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