© 1996 American Heart Association, Inc.
Articles |
Distinct Phenotype of E-Selectin–Deficient Mice
E-Selectin Is Required for Slow Leukocyte Rolling In Vivo
the Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville.
Correspondence to Klaus Ley, MD, University of Virginia School of Medicine, Department of Biomedical Engineering, Box 377, Health Sciences Center, Charlottesville, VA 22908. E-mail kfl3f@virginia.edu.
Leukocyte capture and rolling are mediated by calcium-dependent lectins expressed on most leukocytes (L-selectin) and the vascular endothelium (P- and E-selectin). To study the role of the selectins during inflammation, we have investigated leukocyte rolling in venules of tumor necrosis factor-
(TNF-)–treated mouse cremaster muscles in wild-type mice and gene-targeted mice with homozygous deficiency for L-, P-, or E-selectin (L-/-, P-/-, or E-/-, respectively). TNF- treatment induces expression of E-selectin and increases expression of P-selectin on endothelial cells. Consistent with previous reports of redundant P- and E-selectin function, a combination of monoclonal antibodies (mAbs) against P- and E-selectin (RB40.34 and 9A9, respectively) was necessary to block rolling in wild-type mice. The rolling leukocyte flux fraction (percent rolling cells) in L-/- mice was similar to that in wild-type mice, but rolling in these mice was blocked by a P-selectin mAb. The velocity of rolling leukocytes in TNF-–treated wild-type, P-/-, or L-/- mice was 5 to 10 times slower (3 to 7 µm/s) than during trauma-induced rolling (20 to 50 µm/s). In contrast, leukocytes in venules of TNF-–treated E-/- mice rolled significantly faster (12 to 20 µm/s); the rolling leukocyte flux fraction was more than doubled compared with wild-type, L-/-, or P-/- mice; and the number of adherent leukocytes was reduced. Addition of an E-selectin mAb, but not a P-selectin mAb, increased rolling flux fraction and rolling velocity in wild-type mice. Histological analysis revealed that 90% to 95% of all leukocytes interacting (rolling and adherent) with the venular endothelium in TNF-–treated wild-type, L-/-, P-/-, and E-/- mice were granulocytes. These results identify a previously unrecognized phenotype of E-/- mice by establishing that at the site densities prevailing in vivo, E-selectin is responsible for slow (
5 µm/s) granulocyte rolling. E-selectin–dependent slow rolling drastically increases the transit time of leukocytes rolling through an inflamed tissue and thus aids in targeting leukocytes activated by chemoattractants to the inflammatory microenvironment.
Key Words: venule • microcirculation • inflammation • gene targeting • shear rate
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S. Kanwar, D. A. Steeber, T. F. Tedder, M. J. Hickey, and P. Kubes Overlapping Roles for L-Selectin and P-Selectin in Antigen-Induced Immune Responses in the Microvasculature J. Immunol., March 1, 1999; 162(5): 2709 - 2716. [Abstract] [Full Text] [PDF]
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M. J. Hickey, S. Kanwar, D.-M. McCafferty, D. N. Granger, M. J. Eppihimer, and P. Kubes Varying Roles of E-Selectin and P-Selectin in Different Microvascular Beds in Response to Antigen J. Immunol., January 15, 1999; 162(2): 1137 - 1143. [Abstract] [Full Text] [PDF]
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P. J. Quesenberry and P. S. Becker Stem cell homing: Rolling, crawling, and nesting PNAS, December 22, 1998; 95(26): 15155 - 15157. [Full Text] [PDF]
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E. J. Kunkel, C. L. Ramos, D. A. Steeber, W. Muller, N. Wagner, T. F. Tedder, and K. Ley The Roles of L-Selectin, {beta}7 Integrins, and P-Selectin in Leukocyte Rolling and Adhesion in High Endothelial Venules of Peyer's Patches J. Immunol., September 1, 1998; 161(5): 2449 - 2456. [Abstract] [Full Text] [PDF]
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M. M. Teixeira and P. G. Hellewell Contribution of Endothelial Selectins and {alpha}4 Integrins to Eosinophil Trafficking in Allergic and Nonallergic Inflammatory Reactions in Skin J. Immunol., September 1, 1998; 161(5): 2516 - 2523. [Abstract] [Full Text] [PDF]
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K. Ley, M. Allietta, D. C. Bullard, and S. Morgan Importance of E-Selectin for Firm Leukocyte Adhesion In Vivo Circ. Res., August 10, 1998; 83(3): 287 - 294. [Abstract] [Full Text] [PDF]
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K. Scharffetter-Kochanek, H. Lu, K. Norman, N. van Nood, F. Munoz, S. Grabbe, M. McArthur, I. Lorenzo, S. Kaplan, K. Ley, et al. Spontaneous Skin Ulceration and Defective T Cell Function in CD18 Null Mice J. Exp. Med., July 1, 1998; 188(1): 119 - 131. [Abstract] [Full Text] [PDF]
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D. A. Steeber, M. A. Campbell, A. Basit, K. Ley, and T. F. Tedder Optimal selectin-mediated rolling of leukocytes during inflammation in vivo requires intercellular adhesion molecule-1 expression PNAS, June 23, 1998; 95(13): 7562 - 7567. [Abstract] [Full Text] [PDF]
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U. Jung, C. L. Ramos, D. C. Bullard, and K. Ley Gene-targeted mice reveal importance of L-selectin-dependent rolling for neutrophil adhesion Am J Physiol Heart Circ Physiol, May 1, 1998; 274(5): H1785 - H1791. [Abstract] [Full Text] [PDF]
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E. J. Kunkel, J. E. Chomas, and K. Ley Role of Primary and Secondary Capture for Leukocyte Accumulation In Vivo Circ. Res., January 23, 1998; 82(1): 30 - 38. [Abstract] [Full Text] [PDF]
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K. E. Norman, G. P. Anderson, H. C. Kolb, K. Ley, and B. Ernst Sialyl Lewisx (sLex) and an sLex Mimetic, CGP69669A, Disrupt E-Selectin-Dependent Leukocyte Rolling In Vivo Blood, January 15, 1998; 91(2): 475 - 483. [Abstract] [Full Text] [PDF]
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W. A. Kuziel, S. J. Morgan, T. C. Dawson, S. Griffin, O. Smithies, K. Ley, and N. Maeda Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2 PNAS, October 28, 1997; 94(22): 12053 - 12058. [Abstract] [Full Text] [PDF]
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E. Borges, R. Eytner, T. Moll, M. Steegmaier, M. A. Campbell, K. Ley, H. Mossmann, and D. Vestweber The P-Selectin Glycoprotein Ligand-1 Is Important for Recruitment of Neutrophils Into Inflamed Mouse Peritoneum Blood, September 1, 1997; 90(5): 1934 - 1942. [Abstract] [Full Text] [PDF]
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C. L. Ramos, E. J. Kunkel, M. B. Lawrence, U. Jung, D. Vestweber, R. Bosse, K. W. McIntyre, K. M. Gillooly, C. R. Norton, B. A. Wolitzky, et al. Differential Effect of E-Selectin Antibodies on Neutrophil Rolling and Recruitment to Inflammatory Sites Blood, April 15, 1997; 89(8): 3009 - 3018. [Abstract] [Full Text] [PDF]
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 M. B. Lawrence, G. S. Kansas, E. J. Kunkel, and K. Ley Threshold Levels of Fluid Shear Promote Leukocyte Adhesion through Selectins (CD62L,P,E) J. Cell Biol., February 10, 1997; 136(3): 717 - 727. [Abstract] [Full Text] [PDF]
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M.-C. Huang, O. Zollner, T. Moll, P. Maly, A. D. Thall, J. B. Lowe, and D. Vestweber P-selectin Glycoprotein Ligand-1 and E-selectin Ligand-1 Are Differentially Modified by Fucosyltransferases Fuc-TIV and Fuc-TVII in Mouse Neutrophils J. Biol. Chem., September 29, 2000; 275(40): 31353 - 31360. [Abstract] [Full Text] [PDF]
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M. K. Wild, M.-C. Huang, U. Schulze-Horsel, P. A. van der Merwe, and D. Vestweber Affinity, Kinetics, and Thermodynamics of E-selectin Binding to E-selectin Ligand-1 J. Biol. Chem., August 17, 2001; 276(34): 31602 - 31612. [Abstract] [Full Text] [PDF]
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