LFA‐1 bound to ICAM‐1 homodimer regulates adhesion lifetime and outside‐in signaling

• Published in: The FASEB journal 2006-03, Vol.20 (4), p.A116-A116
• Main Authors: Sarantos, Melissa R, Hayenga, Heather N, Lum, Aaron F H, Raychaudhuri, Subhadip, Staunton, Donald E, Simon, Scott I
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.4.A116

Polymorphonuclear leukocytes (PMN) arrest on inflamed endothelium following transient tethering via selectins and activation and redistribution of integrin receptors. Integrin heterodimer CD11a/CD18 (LFA‐1) shifts conformation following PMN exposure to chemokines presented on the endothelial surface and becomes primed for higher affinity interaction with intercellular adhesion molecule‐1 (ICAM‐1). Redistribution of LFA‐1 and ICAM‐1 into clusters is critical to prolong high avidity adhesion. We have recently reported that allosterically converting LFA‐1 from a high to an intermediate or low affinity state with small molecules results in an exponential decrease in bond lifetime of dimeric ICAM‐1/LFA‐1. These data support the observation that adhesion involves a dynamic regulation of both LFA‐1 conformation and valence in binding to ICAM‐1. We present data showing that LFA‐1 binding to dimeric ICAM‐1 results in local activation of cytoskeletal structures involved in signaling of PMN activation. When LFA‐1 on PMNs was bound to dimeric ICAM‐1, F‐actin and Rap1 expression was amplified at the contact region compared to binding of LFA‐1 to monomeric ICAM‐1. We conclude that LFA‐1 ligation of a homodimer of ICAM‐1 extends bond lifetime through efficient rebinding and may result in associated cytoplasmic signaling via dimeric LFA‐1. Supported by NIH AI47294.