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ARF6 Inhibition Stabilizes the Vasculature and Enhances Survival during Endotoxic Shock

Chadwick T. Davis, Weiquan Zhu, Christopher C. Gibson, Jay A. Bowman-Kirigin, Lise Sorensen, Jing Ling, Huiming Sun, Sutip Navankasattusas and Dean Y. Li
J Immunol June 15, 2014, 192 (12) 6045-6052; DOI: https://doi.org/10.4049/jimmunol.1400309
Chadwick T. Davis
*Department of Human Genetics, University of Utah, Salt Lake City, UT 84112;
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
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Weiquan Zhu
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
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Christopher C. Gibson
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
§Department of Bioengineering, University of Utah, Salt Lake City, UT 84112;
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Jay A. Bowman-Kirigin
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
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Lise Sorensen
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
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Jing Ling
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
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Huiming Sun
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
¶Department of Respiratory and Critical Care Medicine, Jinling Hospital, Clinical School of Nanjing University, Nanjing 210002, China;
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Sutip Navankasattusas
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
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Dean Y. Li
†Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112;
‡Department of Medicine, University of Utah, Salt Lake City, UT 84112;
‖Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112;
#Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City, UT 84112;
**The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China; and
††Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, UT 84112
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Abstract

The vascular endothelium responds to infection by destabilizing endothelial cell–cell junctions to allow fluid and cells to pass into peripheral tissues, facilitating clearance of infection and tissue repair. During sepsis, endotoxin and other proinflammatory molecules induce excessive vascular leak, which can cause organ dysfunction, shock, and death. Current therapies for sepsis are limited to antibiotics and supportive care, which are often insufficient to reduce morbidity and prevent mortality. Previous attempts at blocking inflammatory cytokine responses in humans proved ineffective at reducing the pathologies associated with sepsis, highlighting the need for a new therapeutic strategy. The small GTPase ARF6 is activated by a MyD88–ARNO interaction to induce vascular leak through disruption of endothelial adherens junctions. In this study, we show that the MyD88–ARNO–ARF6–signaling axis is responsible for LPS-induced endothelial permeability and is a destabilizing convergence point used by multiple inflammatory cues. We also show that blocking ARF6 with a peptide construct of its N terminus is sufficient to reduce vascular leak and enhance survival during endotoxic shock, without inhibiting the host cytokine response. Our data highlight the therapeutic potential of blocking ARF6 and reducing vascular leak for the treatment of inflammatory conditions, such as endotoxemia.

Footnotes

  • C.T.D. and D.Y.L. were responsible for project conceptualization, data analysis, and manuscript preparation. C.T.D., W.Z., C.C.G., J.B.-K., L.S., J.L., H.S., S.N., and D.Y.L. were responsible for assay design and data collection. D.Y.L. was responsible for funding the project.

  • This work was supported by the National Institutes of Health, the American Heart Association, the H.A. and Edna Benning Foundation, the Juvenile Diabetes Research Foundation, and the Burroughs Wellcome Fund (to D.Y.L.).

  • Abbreviations used in this article:

    DD
    death domain
    EEA1
    early endosome Ag 1
    HBSS/A
    HBSS supplemented with 1% human serum albumin
    HMVEC-D
    human dermal microvascular endothelial cell
    ID
    intermediate domain
    PMN
    polymorphonuclear leukocyte
    siRNA
    small interfering RNA
    TIR
    Toll/IL-1R
    VE-cadherin
    vascular endothelial cadherin.

  • Received January 31, 2014.
  • Accepted April 16, 2014.
  • Copyright © 2014 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 192 (12)
The Journal of Immunology
Vol. 192, Issue 12
15 Jun 2014
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ARF6 Inhibition Stabilizes the Vasculature and Enhances Survival during Endotoxic Shock
Chadwick T. Davis, Weiquan Zhu, Christopher C. Gibson, Jay A. Bowman-Kirigin, Lise Sorensen, Jing Ling, Huiming Sun, Sutip Navankasattusas, Dean Y. Li
The Journal of Immunology June 15, 2014, 192 (12) 6045-6052; DOI: 10.4049/jimmunol.1400309

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ARF6 Inhibition Stabilizes the Vasculature and Enhances Survival during Endotoxic Shock
Chadwick T. Davis, Weiquan Zhu, Christopher C. Gibson, Jay A. Bowman-Kirigin, Lise Sorensen, Jing Ling, Huiming Sun, Sutip Navankasattusas, Dean Y. Li
The Journal of Immunology June 15, 2014, 192 (12) 6045-6052; DOI: 10.4049/jimmunol.1400309
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