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Src Phosphorylation of Endothelial Cell Surface ICAM-1 Mediates Neutrophil Adhesion and Contributes to the Mechanism of Lung Inflammation

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Title: Src Phosphorylation of Endothelial Cell Surface ICAM-1 Mediates Neutrophil Adhesion and Contributes to the Mechanism of Lung Inflammation
Author(s): Liu, Guoquan; Vogel, Stephen M.; Gao, Xiaopei; Javaid, Kamran; Hu, Guochang; Danilov, Sergei M.; Malik, Asrar B.; Minshall, Richard D.
Subject(s): TNFα ICAM-1 Endothelium PMN Adhesion Src
Abstract: Objective: To determine whether TNFα-induced Src activation and ICAM-1 phosphorylation rapidly increases endothelial cell adhesivity and PMN sequestration independent of de novo ICAM-1 synthesis. Methods and Results: TNFα exposure of mouse lungs for 5 min produced a 3-fold increase in 125I-anti-ICAM-1 mAb binding and 111In oxine-labeled PMN sequestration as well as Src activation, ICAM-1 Tyr518 phosphorylation, and pTyr518-ICAM-1 co-immunoprecipitation with actin. The response was absent in Nox2-/- lungs or following Src inhibition. In COS-7 cells transfected with wild-type (WT), phospho-defective (Y518F), or phospho-mimicking (Y518D) mouse ICAM-1 cDNA constructs, TNFα increased the Bmax of YN1/1.7.4 anti-ICAM-1 mAb binding to WT-ICAM-1 but not to Y518F-ICAM-1 indicating increased binding avidity secondary to ICAM-1 phosphorylation. This effect was mimicked by expression of the Y518DICAM- 1 mutant. TNFα also increased the staining intensity and cell surface clustering of YN1/1.7.4 mAb-labeled WT-ICAM-1 that co-localized with F-actin which was not observed with Y518F-ICAM-1 but was recapitulated with Y518D-ICAM-1. Finally, overexpression of ICAM-1 in mouse lungs significantly increased LPS-induced transvascular albumin leakage and bronchoalveolar lavage PMN counts at 2 and 24 hrs after LPS inhalation compared to lungs expressing Y518F ICAM-1 mutant. Conclusions: Src-dependent phosphorylation of endothelial cell ICAM-1 Tyr518 induces PMN adhesion by promoting ICAM-1 clustering which we propose mediates rapid-phase lung vascular accumulation of PMNs during inflammation.
Issue Date: 2011-06
Publisher: American Heart Association
Citation Info: Liu, G., Vogel, S. M., Gao, X., Javaid, K., Hu, G., Danilov, S. M., Malik, A. B., & Minshall, R. D. 2011. Src Phosphorylation of Endothelial Cell Surface Intercellular Adhesion Molecule-1 Mediates Neutrophil Adhesion and Contributes to the Mechanism of Lung Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(6):1342-U242 . DOI: 10.1161/ATVBAHA.110.222208
Type: Article
Description: Post print version of article may differ from published version. The definitive version is available through American Heart Association at DOI: 10.1161/ATVBAHA.110.222208
URI: http://hdl.handle.net/10027/8439
ISSN: 1079-5642
Sponsor: This work was supported by NIH Grants P01 HL77806, P01 HL60678, and R01 HL71626.
Date Available in INDIGO: 2012-08-07
 

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