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Probing the biomechanical contribution of the endothelium to lymphocyte migration: diapedesis by the path of least resistance.

Martinelli, R; Zeiger, AS; Whitfield, M; Sciuto, TE; Dvorak, A; Van Vliet, KJ; Greenwood, J; (2014) Probing the biomechanical contribution of the endothelium to lymphocyte migration: diapedesis by the path of least resistance. J Cell Sci , 127 (Pt 17) 3720 - 3734. 10.1242/jcs.148619. Green open access

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Abstract

Immune cell trafficking requires the frequent breaching of the endothelial barrier either directly through individual cells ('transcellular' route) or through the inter-endothelial junctions ('paracellular' route). What determines the loci or route of breaching events is an open question with important implications for overall barrier regulation. We hypothesized that basic biomechanical properties of the endothelium might serve as crucial determinants of this process. By altering junctional integrity, cytoskeletal morphology and, consequently, local endothelial cell stiffness of different vascular beds, we could modify the preferred route of diapedesis. In particular, high barrier function was associated with predominantly transcellular migration, whereas negative modulation of junctional integrity resulted in a switch to paracellular diapedesis. Furthermore, we showed that lymphocytes dynamically probe the underlying endothelium by extending invadosome-like protrusions (ILPs) into its surface that deform the nuclear lamina, distort actin filaments and ultimately breach the barrier. Fluorescence imaging and pharmacologic depletion of F-actin demonstrated that lymphocyte barrier breaching efficiency was inversely correlated with local endothelial F-actin density and stiffness. Taken together, these data support the hypothesis that lymphocytes are guided by the mechanical 'path of least resistance' as they transverse the endothelium, a process we term 'tenertaxis'.

Type: Article
Title: Probing the biomechanical contribution of the endothelium to lymphocyte migration: diapedesis by the path of least resistance.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/jcs.148619
Publisher version: http://dx.doi.org/10.1242/jcs.148619
Language: English
Additional information: © 2014. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Actin, Barrier, Endothelium, Leukocyte, Migration, Stiffness
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1447324
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