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

• Published in: Cells (Basel, Switzerland) Switzerland), 2021-01, Vol.10 (2), p.232
• Main Authors: Morsing, Sofia K H, Rademakers, Timo, Brouns, Sanne L N, Stalborch, Anne-Marieke D van, Donners, Marjo M P C, van Buul, Jaap D
• Format: Article
• Language: English
• Subjects: ADAM; Antibodies; Cloning; Deoxyribonucleic acid; Diapedesis; DNA; Endothelial cells; Endothelium; ICAM-1; Inflammation; Intercellular adhesion molecule 1; Leukocyte migration; Leukocytes (neutrophilic); Metalloproteinase; Neutrophils; Proteins; shedding; transmigration
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10020232

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.