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P-selectin primes leukocyte integrin activation during inflammation

Nature Immunology volume 8, pages 882–892 (2007)Cite this article

An Erratum to this article was published on 18 February 2014

This article has been updated

Abstract

Selectins mediate leukocyte rolling and prime leukocytes for integrin-mediated leukocyte adhesion. However, neither the in vivo importance of nor the signaling pathway by which selectin-mediated integrin activation occurs has been determined. We report here that P-selectin-deficient mice manifested impaired leukocyte adhesion, which was 'rescued' by soluble P-selectin. Mechanistically, the cytoplasmic domain of P-selectin glycoprotein ligand 1 formed a constitutive complex with Nef-associated factor 1. After binding of P-selectin, Src kinases phosphorylated Nef-associated factor 1, which recruited the phosphoinositide-3-OH kinase p85-p110δ heterodimer and resulted in activation of leukocyte integrins. Inhibition of this signal-transduction pathway diminished the adhesion of leukocytes to capillary venules and suppressed peritoneal infiltration of leukocytes. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by P-selectin glycoprotein ligand 1.

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Figure 1: Soluble P-selectin restores the adhesion-dependent infiltration of leukocytes in P-selectin-deficient mice.
Figure 2: Binding of the PSGL-1 cytoplasmic tail to Naf1.
Figure 3: Naf1 acts as an adaptor protein linking p85 to PSGL-1.
Figure 4: Obligatory requirement for Naf1 in P-selectin-induced integrin activation.
Figure 5: Requirement for the PSGL-1–Naf1 complex in P-selectin-induced integrin activation.
Figure 6: Essential function of the PI(3)K p85-p110δ heterodimer in P-selectin-induced activation of integrin.

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Change history

  • 13 November 2013

    In the version of this article initially published, in Figure 4b the row labeled 'IB: α-PSGL-1 monomer' is incorrect; it is a duplicate of the row above. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank B. Vanhaesebroeck (Ludwig Institute for Cancer Research) for p110δ-mutant mice; J. Downward (Imperial Cancer Research Fund) for the plasmid encoding p85; and L. Li (Shanghai Institutes for Biological Sciences) for the plasmid encoding PTEN. Supported by the National Science Foundation of China (30370694, 30421005, 30623003, 30400245 and 30630036), the Ministry of Science and Technology of China (2002CB513006, 2006CB943902 and 2006AA02Z169), the Chinese Academy of Sciences (KSCX2-YW-R-67 and KJCX2-YW-H08), the Shanghai Municipal Commission for Science and Technology (04JC14078, 06DZ22032, 55407035 and 058014578) and the National Institutes of Health (RO1AI064743 and P50HL081011).

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  1. Hai-Bo Wang, Jin-Tao Wang, Lei Zhang, Zhen H Geng, Wei-Li Xu and Tao Xu: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Hai-Bo Wang, Jin-Tao Wang, Lei Zhang, Wei-Li Xu, Tao Xu, Xueliang Zhu, Ming Chen & Jian-Guo Geng

  2. Divisions of Hematology, Department of Medicine, Vascular Biology Center, Oncology and Transplantation and Cardiology, University of Minnesota Medical School, Minneapolis, 55455, Minnesota, USA

    Zhen H Geng, Yuqing Huo & Jian-Guo Geng

  3. Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Foundation, Cleveland, 44195, Ohio, USA

    Edward F Plow

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Contributions

H.-B.W., J.-T.W., L.Z., Z.H.G., W.-L.X. and T.X. did the research and analyzed the data; Y.H., X.Z., E.F.P., M.C. and J.-G.G. designed the research; and J.-G.G. wrote the manuscript.

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Correspondence to Ming Chen or Jian-Guo Geng.

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The authors have applied for a patent in China based on this work (application 200710041403.0).

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Wang, HB., Wang, JT., Zhang, L. et al. P-selectin primes leukocyte integrin activation during inflammation. Nat Immunol 8, 882–892 (2007). https://doi.org/10.1038/ni1491

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