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Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock

Nature Medicine volume 13, pages 10421049 (2007) | Download Citation

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Abstract

To identify new components that regulate the inflammatory cascade during sepsis, we characterized the functions of myeloid-related protein-8 (Mrp8, S100A8) and myeloid-related protein-14 (Mrp14, S100A9), two abundant cytoplasmic proteins of phagocytes. We now demonstrate that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli–induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein 88 and activation of interleukin-1 receptor–associated kinase-1 and nuclear factor-κB, resulting in elevated expression of tumor necrosis factor-α (TNF-α). Using phagocytes expressing a nonfunctional Toll-like receptor 4 (TLR4), HEK293 cells transfected with TLR4, CD14 and MD2, and by surface plasmon resonance studies in vitro, we demonstrate that Mrp8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNFα–dependent effects.

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Acknowledgements

We thank C. Sachs, H. Berheide, E. Nattkemper, J. Daalhuisen and K. Övermöhle for excellent technical assistance; P. Björk (Active Biotech, Lund) for performing surface plasmon resonance studies and W. Falk (Department of Internal Medicine I, University of Regensburg, Germany) for providing D. melanogaster Schneider 2 (S2) cells expressing mouseTLR4-MD2. This work was supported by the Interdisciplinary Clinical Research Centre of the University of Muenster (grant Ro20/12/06 to J.R.) and the German Research Foundation (grant SFB293 A16 to J.R.).

Author information

Affiliations

  1. Institute of Experimental Dermatology, University of Münster, D-48129 Münster, Germany.

    • Thomas Vogl
    • , Nadja Leukert
    • , Wolfgang Nacken
    • , Clemens Sorg
    •  & Johannes Roth
  2. Interdisciplinary Center of Clinical Research, University of Münster, D-48129 Münster, Germany.

    • Klaus Tenbrock
    • , Dirk Foell
    •  & Johannes Roth
  3. Department of Pediatrics, University of Münster, D-48129 Münster, Germany.

    • Klaus Tenbrock
    • , Dirk Foell
    •  & Johannes Roth
  4. Institute of Molecular Virology, University of Münster, D-48129 Münster, Germany.

    • Stephan Ludwig
    •  & Christina Ehrhardt
  5. Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

    • Marieke A D van Zoelen
    •  & Tom van der Poll

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Contributions

T.V. designed the study and the experiments, performed animal studies and experiments and wrote the manuscript. K.T. performed the ChIP experiments and analyzed data. S.L. and C.E. performed cell-culture experiments and transfection studies. N.L. and D.F. performed the immunohistological analyses and flow cytometry. M.A.D.v.Z. and T.v.d.P. performed and analyzed animal studies. W.N. generated the Mrp14−/− mice and assisted with the animal studies. C.S. assisted with the design of experiments. J.R. designed the study and experiments, analyzed data, supervised the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Johannes Roth.

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DOI

https://doi.org/10.1038/nm1638

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