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

Publication date: 17 January 2017
Source:Cell Reports, Volume 18, Issue 3
Author(s): 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
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.

Graphical abstract

Teaser

The mechanisms by which leukocytes squeeze through endothelial barriers have been elusive. Here, Barzilai et al. find that leukocytes use their nuclear lobes to generate gaps and pores in between and inside the endothelial cells they cross using the rapid turnover of endothelial actin filaments rather than endothelial contraction.


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