title: Probing the biomechanical contribution of the endothelium to lymphocyte migration: diapedesis by the path of least resistance.
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'.
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA Department of Cell Biology, Institute of Ophthalmology, UCL, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Martinelli
authors.affiliation: Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Zeiger
authors.affiliation: Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whitfield
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tracey E
authors.initials: TE
authors.lastname: Sciuto
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Dvorak
authors.affiliation: Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Krystyn J
authors.initials: KJ
authors.lastname: Van Vliet
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, UCL, 11-43 Bath Street, London EC1V 9EL, UK j.greenwood@ucl.ac.uk ccarman@bidmc.harvard.edu.
authors.forename: John
authors.initials: J
authors.lastname: Greenwood
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA j.greenwood@ucl.ac.uk ccarman@bidmc.harvard.edu.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Carman
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001696:Biomechanical Phenomena; D002465:Cell Movement / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D051381:Rats
chemical_list: D000199:Actins
keywords: Actin; Barrier; Endothelium; Leukocyte; Migration; Stiffness