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Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating β2 integrins

Nature Immunology volume 9, pages 880–886 (2008)Cite this article

Abstract

Nonmuscle myosin light-chain kinase (MYLK) mediates increased lung vascular endothelial permeability in lipopolysaccharide-induced lung inflammatory injury, the chief cause of the acute respiratory distress syndrome. In a lung injury model, we demonstrate here that MYLK was also essential for neutrophil transmigration, but that this function was mostly independent of myosin II regulatory light chain, the only known substrate of MYLK. Instead, MYLK in neutrophils was required for the recruitment and activation of the tyrosine kinase Pyk2, which mediated full activation of β2 integrins. Our results demonstrate that MYLK-mediated activation of β2 integrins through Pyk2 links β2 integrin signaling to the actin motile machinery of neutrophils.

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Figure 1: Ex vivo LPS-induced lung injury and edema formation.
Figure 2: Loss of MYLK function fails to prevent myosin II activation.
Figure 3: Activation of β2 integrin in neutrophils.
Figure 4: Tyrosine kinase activation and interaction with β2 integrin.
Figure 5: The interaction of β2 integrin and the cytoskeleton in neutrophils.

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Acknowledgements

We thank D.M. Watterson (Northwestern University) for Mylk−/− mice; X. Zhu (University of Chicago) for Pyk2 cDNA; X. Zhu, X. Du, R. Ye and Y. Li for suggestions and reading the manuscript; R.A. Skidgel and T. Sharma (Department of Pharmacology Molecular Core Facility) for making glutathione S-transferase–Pyk2; and G. Liu, C. Gilbert, S. Debra and K. Javaid for technical assistance. Supported by the University of Illinois (J.X.) and the US National Institutes of Health (HL77806 and HL46350 to A.B.M.).

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Author notes

  1. Jingsong Xu and Xiao-Pei Gao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.,

    Jingsong Xu, Xiao-Pei Gao, Ramaswamy Ramchandran, You-Yang Zhao, Stephen M Vogel & Asrar B Malik

  2. Department of Dermatology, and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.,

    Jingsong Xu

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  1. Jingsong Xu
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Contributions

J.X. designed experiments, did research and wrote the paper; A.B.M. designed research and wrote the paper; X.-P.G. designed and did research; and R.R., Y.-Y.Z. and S.M.V. did research.

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Correspondence to Jingsong Xu or Asrar B Malik.

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Xu, J., Gao, XP., Ramchandran, R. et al. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating β2 integrins. Nat Immunol 9, 880–886 (2008). https://doi.org/10.1038/ni.1628

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