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ADAM10-Mediated Cleavage of ICAM-1 Is Involved in Neutrophil Transendothelial Migration

Molecular Cell Biology Lab, Department Molecular and Cellular Homeostasis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands
Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
Leeuwenhoek Centre for Advanced Microscopy (LCAM), Section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS), University of Amsterdam, 1066 CX Amsterdam, The Netherlands
Authors to whom correspondence should be addressed.
These authors equally contributed to the paper.
Academic Editors: Patric Turowski and Silvia Dragoni
Cells 2021, 10(2), 232;
Received: 20 August 2020 / Revised: 12 January 2021 / Accepted: 19 January 2021 / Published: 25 January 2021
(This article belongs to the Special Issue Vascular Signalling)
To efficiently cross the endothelial barrier during inflammation, neutrophils first firmly adhere to the endothelial surface using the endothelial adhesion molecule ICAM-1. Upon actual transmigration, the release from ICAM-1 is required. While Integrin LFA1/Mac1 de-activation is one described mechanism that leads to this, direct cleavage of ICAM-1 from the endothelium represents a second option. We found that a disintegrin and metalloprotease 10 (ADAM10) cleaves the extracellular domain of ICAM-1 from the endothelial surface. Silencing or inhibiting endothelial ADAM10 impaired the efficiency of neutrophils to cross the endothelium, suggesting that neutrophils use endothelial ADAM10 to dissociate from ICAM-1. Indeed, when measuring transmigration kinetics, neutrophils took almost twice as much time to finish the diapedesis step when ADAM10 was silenced. Importantly, we found increased levels of ICAM-1 on the transmigrating neutrophils when crossing an endothelial monolayer where such increased levels were not detected when neutrophils crossed bare filters. Using ICAM-1-GFP-expressing endothelial cells, we show that ICAM-1 presence on the neutrophils can also occur by membrane transfer from the endothelium to the neutrophil. Based on these findings, we conclude that endothelial ADAM10 contributes in part to neutrophil transendothelial migration by cleaving ICAM-1, thereby supporting the release of neutrophils from the endothelium during the final diapedesis step. View Full-Text
Keywords: transmigration; ICAM-1; endothelium; ADAM; shedding transmigration; ICAM-1; endothelium; ADAM; shedding
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    Description: Figure S1. (A) ECs were applied to flow in the TEM flow chamber and perfused with primary human neutrophils. Phenotype of the neutrophils detected with DIC microscopy discriminates between a crawling neutrophil (bright dot phenotype, arrow) and a transmigrated neutrophil (dark-grey phenotype, arrowhead). (B) ECs were transfected with ICAM-GFP as indicated. >95% of all endothelial cells were transfected. (C) ImageStream example of positive neutrophils, as indicated. Neutrophils were additionally incubated with an ICAM-1-antibody (red). (D) Schematic overview of proposed mechanism by which shedding of the extracellular domain of ICAM-1 by endothelial ADAM10 is involved in neutrophil diapedesis.
MDPI and ACS Style

Morsing, S.K.H.; Rademakers, T.; Brouns, S.L.N.; van Stalborch, A.-M.D.; Donners, M.M.P.C.; van Buul, J.D. ADAM10-Mediated Cleavage of ICAM-1 Is Involved in Neutrophil Transendothelial Migration. Cells 2021, 10, 232.

AMA Style

Morsing SKH, Rademakers T, Brouns SLN, van Stalborch A-MD, Donners MMPC, van Buul JD. ADAM10-Mediated Cleavage of ICAM-1 Is Involved in Neutrophil Transendothelial Migration. Cells. 2021; 10(2):232.

Chicago/Turabian Style

Morsing, Sofia K.H., Timo Rademakers, Sanne L.N. Brouns, Anne-Marieke D. van Stalborch, Marjo M.P.C. Donners, and Jaap D. van Buul 2021. "ADAM10-Mediated Cleavage of ICAM-1 Is Involved in Neutrophil Transendothelial Migration" Cells 10, no. 2: 232.

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