Letter | Published:

Interleukin receptor activates a MYD88–ARNO–ARF6 cascade to disrupt vascular stability

Nature volume 492, pages 252255 (13 December 2012) | Download Citation

Abstract

The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-dependent transcriptional pathway that results in inflammatory-cell activation and recruitment1,2,3,4. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response5,6. Paradoxically, the cytokines vital to a successful immune defence also have disruptive effects on endothelial cell–cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture7,8,9. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1β on endothelial stability in a human in vitro cell model are NF-κB independent and are instead the result of signalling through the small GTPase ADP-ribosylation factor 6 (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as CYTH2). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, and thus propose MYD88–ARNO–ARF6 as a proximal IL-1β signalling pathway distinct from that mediated by NF-κB. Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.

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Acknowledgements

We thank D. Lim and T. Mleynek for graphical assistance, G. Zimmerman and J. Kaplan for reading the manuscript, S. Odelberg for reading the manuscript and statistical analysis, J. Ling for help with immunostaining, R. Campbell and A. Weyrich for providing primary human blood cells, C. Rodesch and the University of Utah Cell Imaging/Fluorescence Facility as well as the University of Utah Flow Cytometry Facility, and M. P. Revelo for help with pathology. D.Y.L. and his laboratory were funded by grants from the National Heart, Lung, and Blood Institute; Burroughs Wellcome Fund; Juvenile Diabetes Research Foundation; NIAID Rocky Mountain Regional Center of Excellence in Biodefense and Emerging Infectious Disease; the American Asthma Foundation; and the Department of Defense. D.Y.L. is the HA and Edna Benning Endowed Professor of Medicine and Cardiology.

Author information

Author notes

    • Weiquan Zhu
    • , Nyall R. London
    •  & Christopher C. Gibson

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine, University of Utah, Salt Lake City, Utah 84112, USA

    • Weiquan Zhu
    • , Nyall R. London
    • , Jinping Guo
    • , Matthew C. P. Smith
    • , Kirk R. Thomas
    •  & Dean Y. Li
  2. Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA

    • Weiquan Zhu
    • , Nyall R. London
    • , Christopher C. Gibson
    • , Chadwick T. Davis
    • , Lise K. Sorensen
    • , Dallas S. Shi
    • , Jinping Guo
    • , Matthew C. P. Smith
    • , Allie H. Grossmann
    • , Kirk R. Thomas
    •  & Dean Y. Li
  3. Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112, USA

    • Nyall R. London
    • , Matthew C. P. Smith
    •  & Dean Y. Li
  4. Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA

    • Christopher C. Gibson
  5. Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA

    • Chadwick T. Davis
    •  & Dallas S. Shi
  6. Navigen Inc, Salt Lake City, Utah 84112, USA

    • Zongzhong Tong
  7. Department of Anatomy, Second Military Medical University, Shanghai 200433, China

    • Jinping Guo
  8. Department of Pathology, University of Utah, Salt Lake City, Utah 84112, USA

    • Allie H. Grossmann
  9. Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, Utah 84112, USA

    • Dean Y. Li
  10. 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

    • Dean Y. Li

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Contributions

W.Z., N.R.L., C.C.G. and D.Y.L. were responsible for project conceptualization, experimental design, data analysis and manuscript preparation. W.Z., C.C.G., C.T.D., Z.T., L.K.S., D.S.S. and J.G. performed and collected data for in vitro experiments. N.R.L. collected data for in vivo experiments. C.C.G. developed software techniques for immunofluorescence analysis. M.C.P.S. performed flow cytometry experiments. Z.T. and K.R.T. made constructs and adenoviruses. A.H.G. provided histology and pathology expertise. D.Y.L. was responsible for funding the project.

Competing interests

The University of Utah has filed intellectual property concerning targeting signalling pathways to treat inflammatory arthritis. The University of Utah has licensed technology to Navigen, a biotechnology company owned in part by the University of Utah Research Foundation. N.R.L. and W.Z. are paid consultants for Navigen and D.Y.L. is a co-founder of Navigen.

Corresponding author

Correspondence to Dean Y. Li.

Supplementary information

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    Supplementary Information

    This file contains Supplementary Figures 1-9, Supplementary Methods and Supplementary References. This file was replaced on December 19th 2012.

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DOI

https://doi.org/10.1038/nature11603

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