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Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation

Nature Chemical Biology volume 7, pages 7577 (2011) | Download Citation

Abstract

The signaling mechanisms leading to the formation of neutrophil extracellular traps (NETs), relevant in infections, sepsis and autoimmune diseases, are poorly understood. Neutrophils are not amenable to studies with conventional genetic techniques. Using a new chemical genetic analysis we show that the Raf-MEK-ERK pathway is involved in NET formation through activation of NADPH oxidase and upregulation of antiapoptotic proteins. We identify potential targets for drugs addressing NET-associated diseases.

  • Compound C12H8ClI

    Diphenyleneiodonium chloride

  • Compound C15H8Br2INO2

    GW5074

  • Compound C18H16N6S2

    U0126

  • Compound C28H26N4O3

    Staurosporine

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Acknowledgements

We thank K. Laettig for acquiring the automated microscopy data, S. Jagadeesan for providing H. pylori cultures and help with the biochemistry of ERK, and C. Chaput for helping with the phagocytosis assay (all from Max Planck Institute for Infection Biology). We thank M. Rusch, C. Hedberg, R. Bon and A. Stigter (Max Plank Institute for Molecular Physiology) for providing the palmostatin B, BMS3 and ABT compounds.

Author information

Affiliations

  1. Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin.

    • Abdul Hakkim
    • , Tobias A Fuchs
    •  & Arturo Zychlinsky
  2. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.

    • Nancy E Martinez
    • , Heino Prinz
    •  & Herbert Waldmann
  3. Faculty of Chemistry, Technische Universität Dortmund, Dortmund, Germany.

    • Nancy E Martinez
    •  & Herbert Waldmann
  4. Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin.

    • Simone Hess

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Contributions

A.H., T.A.F., A.Z. and H.W. designed the research and wrote the manuscript. S.H. did the automated microscopy, and H.P. automated the chemical screen protocol. A.H., T.A.F. and N.E.M. performed the research.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Arturo Zychlinsky or Herbert Waldmann.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Methods, Supplementary Figures 1–6 and Supplementary Table 1

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DOI

https://doi.org/10.1038/nchembio.496

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