Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.
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.
London
Nyall R
NR
Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Zhu
Weiquan
W
Bozza
Fernando A
FA
Smith
Matthew C P
MC
Greif
Daniel M
DM
Sorensen
Lise K
LK
Chen
Luming
L
Kaminoh
Yuuki
Y
Chan
Aubrey C
AC
Passi
Samuel F
SF
Day
Craig W
CW
Barnard
Dale L
DL
Zimmerman
Guy A
GA
Krasnow
Mark A
MA
Li
Dean Y
DY
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D051177:Catenins / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D000095002:Delta Catenin; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
D015820:Cadherins; D051177:Catenins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D000095002:Delta Catenin; D000098552:Slit Homolog 2 Protein; C462951:ROBO4 protein, human; D000097905:Roundabout Proteins; C540792:Robo4 protein, mouse