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

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.

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Figure 1: Quantification of cell viability and nuclear morphology.
Figure 2: Identification of the Raf-MEK-ERK pathway during NET formation.

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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.

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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.

Corresponding authors

Correspondence to Arturo Zychlinsky or Herbert Waldmann.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–6 and Supplementary Table 1 (PDF 2425 kb)

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Hakkim, A., Fuchs, T., Martinez, N. et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol 7, 75–77 (2011). https://doi.org/10.1038/nchembio.496

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