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Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases

Abstract

To kill invading bacteria, neutrophils must interpret spatial cues, migrate and reach target sites. Although the initiation of chemotactic migration has been extensively studied, little is known about its termination. Here we found that two mitogen-activated protein kinases (MAPKs) had opposing roles in neutrophil trafficking. The extracellular signal–regulated kinase Erk potentiated activity of the G protein–coupled receptor kinase GRK2 and inhibited neutrophil migration, whereas the MAPK p38 acted as a noncanonical GRK that phosphorylated the formyl peptide receptor FPR1 and facilitated neutrophil migration by blocking GRK2 function. Therefore, the dynamic balance between Erk and p38 controlled neutrophil 'stop' and 'go' activity, which ensured that neutrophils reached their final destination as the first line of host defense.

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Figure 1: Erk and p38 have opposite roles in neutrophil chemotaxis.
Figure 2: Concentration-dependent switch for neutrophil chemotaxis and transmigration.
Figure 3: Inhibition of Erk or enhancement of p38 restores cell migration at high concentrations of fMLF.
Figure 4: Receptor internalization acts as a stop signal for directional migration.
Figure 5: Differences in the regulation of FPR1 internalization by p38 and Erk.
Figure 6: GRK2 mediates the stop signal for neutrophil migration.
Figure 7: Phosphorylation of FPR1 by p38.
Figure 8: Differences in the activation of Erk and p38.

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Acknowledgements

We thank X. Du, B. Gantner (University of Illinois at Chicago), S. Wang (Peking University) and S. Chen (University of Iowa) for discussions, E.R. Prossnitz (University of New Mexico) for the FPR1-ΔST construct and K. Otsu (Osaka University) for permission to use mice with loxP-flanked Mapk14. Supported by the US National Institutes of Health (HL095716 and AI033503), the Chinese Academy of Sciences (KSCX-W-R-66 and KSCX2-YW-R-156), the Natural Science Foundation of China (30630037 and 31070956) and the National Basic Research Program of China (2010CB945301 and 2011CB710900).

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Authors

Contributions

X.L., B.M., Y.L., R.D.Y. and J.X. designed the research; X.L., B.M., H.T., T.Y., B.S. and G.W. did the experiments; X.L., B.M. and J.X. analyzed data; A.B.M., R.D.M. and Y.Z. contributed new reagents and tools; and X.L., B.M., A.B.M., Y.L., R.D.Y. and J.X. wrote the paper.

Corresponding authors

Correspondence to Richard D Ye or Jingsong Xu.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Tables 1–2 (PDF 12697 kb)

Supplementary Video 1

Control HL60 cells migrated in the 100 nM fMLP gradient. (AVI 3844 kb)

Supplementary Video 2

SB203580-treated HL60 cells migrated in the 100 nM fMLP gradient. (AVI 4667 kb)

Supplementary Video 3

PD98059-treated HL60 cells migrated in the 100 nM fMLP gradient. (AVI 4379 kb)

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Liu, X., Ma, B., Malik, A. et al. Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases. Nat Immunol 13, 457–464 (2012). https://doi.org/10.1038/ni.2258

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