Leukocytes Breach Endothelial Barriers by Insertion of Nuclear Lobes and Disassembly of Endothelial Actin Filaments

Sagi Barzilai, Sandeep Kumar Yadav, Steven Morrell, Francesco Roncato, Eugenia Klein, Liat Stoler-Barak, Ofra Golani, Sara W. Feigelson, Assaf Zemel, Sussan Nourshargh, Ronen Alon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

The endothelial cytoskeleton is a barrier for leukocyte transendothelial migration (TEM). Mononuclear and polymorphonuclear leukocytes generate gaps of similar micron-scale size when squeezing through inflamed endothelial barriers in vitro and in vivo. To elucidate how leukocytes squeeze through these barriers, we co-tracked the endothelial actin filaments and leukocyte nuclei in real time. Nuclear squeezing involved either preexistent or de novo-generated lobes inserted into the leukocyte lamellipodia. Leukocyte nuclei reversibly bent the endothelial actin stress fibers. Surprisingly, formation of both paracellular gaps and transcellular pores by squeezing leukocytes did not require Rho kinase or myosin II-mediated endothelial contractility. Electron-microscopic analysis suggested that nuclear squeezing displaced without condensing the endothelial actin filaments. Blocking endothelial actin turnover abolished leukocyte nuclear squeezing, whereas increasing actin filament density did not. We propose that leukocyte nuclei must disassemble the thin endothelial actin filaments interlaced between endothelial stress fibers in order to complete TEM.

Original languageAmerican English
Pages (from-to)685-699
Number of pages15
JournalCell Reports
Volume18
Issue number3
DOIs
StatePublished - 17 Jan 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s)

Keywords

  • adhesion
  • inflammation
  • leukocyte trafficking
  • migration
  • shear flow
  • vasculature

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