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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2101-2111. Prepublished online as a Blood First Edition Paper on November 3, 2005November 8, 2005; DOI 10.1182/blood-2005-06-2303. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: 2005-06-2303v1 2005-06-2303v2 107/5/2101    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Green, C. E Articles by Simon, S. I Search for Related Content PubMed PubMed Citation Articles by Green, C. E Articles by Simon, S. I Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 9, 2005 Accepted October 13, 2005 Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium Chad E Green, Ulrich Y Schaff, Melissa R Sarantos, Aaron F Lum, Donald E Staunton, and Scott I Simon* Davis Department of Biomedical Engineering, Genome and Biomedical Sciences Facility, University of California, Davis, CA, USA ICOS Corporation, Bothell, WA, USA * Corresponding author; email: sisimon{at}ucdavis.edu. Polymorphonuclear leukocyte (PMN) recruitment to vascular endothelium during acute inflammation involves cooperation between selectins, G-proteins and 2-integrins. LFA-1 (CD11a/CD18) affinity correlates with specific adhesion functions as a shift from low to intermediate affinity supports rolling on ICAM-1, whereas high affinity is associated with shear resistant leukocyte arrest. We imaged PMN adhesion on cytokine inflamed endothelium in a parallel plate flow chamber in order to define the dynamics of 2-integrin function during recruitment and transmigration. Following arrest on inflamed endothelium, high affinity LFA-1 aligned along the uropod-pseudopod major axis which was essential for efficient neutrophil polarization and subsequent transmigration. An allosteric small molecule inhibitor targeted to the I domain stabilized LFA-1 in an intermediate affinity conformation, which supported neutrophil rolling but inhibited cell polarization and abrogated transmigration. We conclude that a shift in LFA-1 from intermediate to high affinity during the transition from rolling to arrest provides contact mediated signaling and guidance necessary for PMN transmigration on inflamed endothelium. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Phillipson, B. Heit, S. A. Parsons, B. Petri, S. C. Mullaly, P. Colarusso, R. M. Gower, G. Neely, S. I. Simon, and P. Kubes Vav1 Is Essential for Mechanotactic Crawling and Migration of Neutrophils out of the Inflamed Microvasculature J. Immunol., June 1, 2009; 182(11): 6870 - 6878. [Abstract] [Full Text] [PDF] M. R. Sarantos, H. Zhang, U. Y. Schaff, N. Dixit, H. N. Hayenga, C. A. Lowell, and S. I. Simon Transmigration of Neutrophils across Inflamed Endothelium Is Signaled through LFA-1 and Src Family Kinase J. Immunol., December 15, 2008; 181(12): 8660 - 8669. [Abstract] [Full Text] [PDF] R. Zennadi, A. Chien, K. Xu, M. Batchvarova, and M. J. Telen Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium Blood, October 15, 2008; 112(8): 3474 - 3483. [Abstract] [Full Text] [PDF] U. Schaff, P. E. Mattila, S. I. Simon, and B. Walcheck Neutrophil adhesion to E-selectin under shear promotes the redistribution and co-clustering of ADAM17 and its proteolytic substrate L-selectin J. Leukoc. Biol., January 1, 2008; 83(1): 99 - 105. [Abstract] [Full Text] [PDF] C. Sadhu, H. J. Ting, B. Lipsky, K. Hensley, L. F. Garcia-Martinez, S. I. Simon, and D. E. Staunton CD11c/CD18: novel ligands and a role in delayed-type hypersensitivity J. Leukoc. Biol., June 1, 2007; 81(6): 1395 - 1403. [Abstract] [Full Text] [PDF] R. Castriconi, A. Dondero, C. Cantoni, M. Della Chiesa, C. Prato, M. Nanni, M. Fiorini, L. Notarangelo, S. Parolini, L. Moretta, et al. Functional characterization of natural killer cells in type I leukocyte adhesion deficiency Blood, June 1, 2007; 109(11): 4873 - 4881. [Abstract] [Full Text] [PDF] M. Sircar, P. F. Bradfield, M. Aurrand-Lions, R. J. Fish, P. Alcaide, L. Yang, G. Newton, D. Lamont, S. Sehrawat, T. Mayadas, et al. Neutrophil Transmigration under Shear Flow Conditions In Vitro Is Junctional Adhesion Molecule-C Independent J. Immunol., May 1, 2007; 178(9): 5879 - 5887. [Abstract] [Full Text] [PDF] S. C. Fagerholm, M. Varis, M. Stefanidakis, T. J. Hilden, and C. G. Gahmberg {alpha}-Chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation Blood, November 15, 2006; 108(10): 3379 - 3386. [Abstract] [Full Text] [PDF] S. Devaraj, B. Davis, S. I. Simon, and I. Jialal CRP promotes monocyte-endothelial cell adhesion via Fc{gamma} receptors in human aortic endothelial cells under static and shear flow conditions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1170 - H1176. [Abstract] [Full Text] [PDF]

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