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Neutrophil Recruitment under Shear Flow: It's All about Endothelial Cell Rings and Gaps

Authors

  • PILAR ALCAIDE,

    1. Center for Excellence in Vascular Biology, Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • SCOTT AUERBACH,

    1. Center for Excellence in Vascular Biology, Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • FRANCIS W. LUSCINSKAS

    Corresponding author
    1. Center for Excellence in Vascular Biology, Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • This work was supported by NIH grants HL36028 and HL53993 and a NIH NRSA training award F32 HL086217 (SA).

Address correspondence to: Francis W. Luscinskas, Center for Excellence in Vascular Biology, Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB752, Boston, MA, 02115, USA. E-mail: fluscinskas@rics.bwh.harvard.edu

ABSTRACT

Leukocyte recruitment to tissues and organs is an essential component of host defense. The molecular mechanisms controlling this process are complex and remain under active investigation. The combination of biochemical techniques and live cell imaging using in vivo and in vitro flow-model approaches have shed light on several aspects of neutrophil transmigration through the vascular endothelial lining of blood vessels. Here, we focus on the role of adhesion molecule signaling in endothelial cells and their downstream targets during the process of transendothelial migration at cell-cell borders (paracellular transmigration). An emerging model involves the leukocyte β2 integrin engagement of endothelial cell ICAM-1, which triggers integrin-ICAM-1 clustering (rings) and stabilizes leukocyte adhesion at cell-cell junctions. This step recruits nonreceptor tyrosine kinases that phosphorylate key tyrosine residues in the cytoplasmic tail of VE-cadherin, which destabilizes its linkage to catenins and the actin cytoskeleton, triggering the transient opening of VE-cadherin homodimers to form a gap in the cell junction, through which the neutrophil transmigrates. Interestingly, the signaling events that lead to neutrophil transmigration occur independently of shear flow in vitro.

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