Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Oct 15;102(8):1526–1533. doi: 10.1172/JCI119893

Transit time of leukocytes rolling through venules controls cytokine-induced inflammatory cell recruitment in vivo.

U Jung 1, K E Norman 1, K Scharffetter-Kochanek 1, A L Beaudet 1, K Ley 1
PMCID: PMC509002  PMID: 9788965

Abstract

Leukocyte recruitment requires leukocyte rolling, activation, firm adhesion, and transmigration. Injection of the proinflammatory cytokine TNF-alpha induces expression of E-selectin, interleukin-8, and other adhesion molecules and chemoattractants on the endothelial surface. TNF-alpha- treated CD18 null mouse cremaster muscle venules show increased leukocyte rolling velocity and reduced leukocyte recruitment efficiency. Leukocyte recruitment in CD18 null but not wild-type mice is significantly blocked by an mAb to E-selectin. To understand this overlap between adhesion events previously considered separate, we introduce a quantitative analysis of the efficiency of induction of rolling, conversion of rolling to adhesion, and of adhesion to transmigration. We find that CD18 and E-selectin cooperate to control the time a leukocyte needs to roll through an inflamed area and to convert rolling to firm adhesion. Leukocyte rolling time, defined as the time it takes for a rolling leukocyte to pass through a defined length of a vessel segment, emerges as a unifying parameter determining the efficiency of inducing firm adhesion, which is a rate-limiting step controlling leukocyte recruitment in inflammation. We conclude that leukocytes integrate chemoattractant signals while rolling along the endothelial surface until they reach a critical level of activation and become firmly adherent.

Full Text

The Full Text of this article is available as a PDF (247.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alon R., Hammer D. A., Springer T. A. Lifetime of the P-selectin-carbohydrate bond and its response to tensile force in hydrodynamic flow. Nature. 1995 Apr 6;374(6522):539–542. doi: 10.1038/374539a0. [DOI] [PubMed] [Google Scholar]
  2. Arfors K. E., Lundberg C., Lindbom L., Lundberg K., Beatty P. G., Harlan J. M. A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood. 1987 Jan;69(1):338–340. [PubMed] [Google Scholar]
  3. Burns A. R., Walker D. C., Brown E. S., Thurmon L. T., Bowden R. A., Keese C. R., Simon S. I., Entman M. L., Smith C. W. Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners. J Immunol. 1997 Sep 15;159(6):2893–2903. [PubMed] [Google Scholar]
  4. Bussolino F., Camussi G., Baglioni C. Synthesis and release of platelet-activating factor by human vascular endothelial cells treated with tumor necrosis factor or interleukin 1 alpha. J Biol Chem. 1988 Aug 25;263(24):11856–11861. [PubMed] [Google Scholar]
  5. Butcher E. C. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991 Dec 20;67(6):1033–1036. doi: 10.1016/0092-8674(91)90279-8. [DOI] [PubMed] [Google Scholar]
  6. Damiano E. R., Westheider J., Tözeren A., Ley K. Variation in the velocity, deformation, and adhesion energy density of leukocytes rolling within venules. Circ Res. 1996 Dec;79(6):1122–1130. doi: 10.1161/01.res.79.6.1122. [DOI] [PubMed] [Google Scholar]
  7. Drazen J. M., Arm J. P., Austen K. F. Sorting out the cytokines of asthma. J Exp Med. 1996 Jan 1;183(1):1–5. doi: 10.1084/jem.183.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Frenette P. S., Mayadas T. N., Rayburn H., Hynes R. O., Wagner D. D. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell. 1996 Feb 23;84(4):563–574. doi: 10.1016/s0092-8674(00)81032-6. [DOI] [PubMed] [Google Scholar]
  9. Gaboury J. P., Kubes P. Reductions in physiologic shear rates lead to CD11/CD18-dependent, selectin-independent leukocyte rolling in vivo. Blood. 1994 Jan 15;83(2):345–350. [PubMed] [Google Scholar]
  10. Huber A. R., Kunkel S. L., Todd R. F., 3rd, Weiss S. J. Regulation of transendothelial neutrophil migration by endogenous interleukin-8. Science. 1991 Oct 4;254(5028):99–102. doi: 10.1126/science.1718038. [DOI] [PubMed] [Google Scholar]
  11. Jung U., Bullard D. C., Tedder T. F., Ley K. Velocity differences between L- and P-selectin-dependent neutrophil rolling in venules of mouse cremaster muscle in vivo. Am J Physiol. 1996 Dec;271(6 Pt 2):H2740–H2747. doi: 10.1152/ajpheart.1996.271.6.H2740. [DOI] [PubMed] [Google Scholar]
  12. Jung U., Ley K. Regulation of E-selectin, P-selectin, and intercellular adhesion molecule 1 expression in mouse cremaster muscle vasculature. Microcirculation. 1997 Jun;4(2):311–319. doi: 10.3109/10739689709146794. [DOI] [PubMed] [Google Scholar]
  13. Kansas G. S. Selectins and their ligands: current concepts and controversies. Blood. 1996 Nov 1;88(9):3259–3287. [PubMed] [Google Scholar]
  14. Kanwar S., Bullard D. C., Hickey M. J., Smith C. W., Beaudet A. L., Wolitzky B. A., Kubes P. The association between alpha4-integrin, P-selectin, and E-selectin in an allergic model of inflammation. J Exp Med. 1997 Mar 17;185(6):1077–1087. doi: 10.1084/jem.185.6.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kunkel E. J., Jung U., Bullard D. C., Norman K. E., Wolitzky B. A., Vestweber D., Beaudet A. L., Ley K. Absence of trauma-induced leukocyte rolling in mice deficient in both P-selectin and intercellular adhesion molecule 1. J Exp Med. 1996 Jan 1;183(1):57–65. doi: 10.1084/jem.183.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kunkel E. J., Ley K. Distinct phenotype of E-selectin-deficient mice. E-selectin is required for slow leukocyte rolling in vivo. Circ Res. 1996 Dec;79(6):1196–1204. doi: 10.1161/01.res.79.6.1196. [DOI] [PubMed] [Google Scholar]
  17. Lawrence M. B., Smith C. W., Eskin S. G., McIntire L. V. Effect of venous shear stress on CD18-mediated neutrophil adhesion to cultured endothelium. Blood. 1990 Jan 1;75(1):227–237. [PubMed] [Google Scholar]
  18. Lawrence M. B., Springer T. A. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 1991 May 31;65(5):859–873. doi: 10.1016/0092-8674(91)90393-d. [DOI] [PubMed] [Google Scholar]
  19. Ley K., Allietta M., Bullard D. C., Morgan S. Importance of E-selectin for firm leukocyte adhesion in vivo. Circ Res. 1998 Aug 10;83(3):287–294. doi: 10.1161/01.res.83.3.287. [DOI] [PubMed] [Google Scholar]
  20. Ley K., Bullard D. C., Arbonés M. L., Bosse R., Vestweber D., Tedder T. F., Beaudet A. L. Sequential contribution of L- and P-selectin to leukocyte rolling in vivo. J Exp Med. 1995 Feb 1;181(2):669–675. doi: 10.1084/jem.181.2.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lipowsky H. H., Zweifach B. W. Application of the "two-slit" photometric technique to the measurement of microvascular volumetric flow rates. Microvasc Res. 1978 Jan;15(1):93–101. doi: 10.1016/0026-2862(78)90009-2. [DOI] [PubMed] [Google Scholar]
  22. Lu H., Smith C. W., Perrard J., Bullard D., Tang L., Shappell S. B., Entman M. L., Beaudet A. L., Ballantyne C. M. LFA-1 is sufficient in mediating neutrophil emigration in Mac-1-deficient mice. J Clin Invest. 1997 Mar 15;99(6):1340–1350. doi: 10.1172/JCI119293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mayadas T. N., Johnson R. C., Rayburn H., Hynes R. O., Wagner D. D. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell. 1993 Aug 13;74(3):541–554. doi: 10.1016/0092-8674(93)80055-j. [DOI] [PubMed] [Google Scholar]
  24. Middleton J., Neil S., Wintle J., Clark-Lewis I., Moore H., Lam C., Auer M., Hub E., Rot A. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell. 1997 Oct 31;91(3):385–395. doi: 10.1016/s0092-8674(00)80422-5. [DOI] [PubMed] [Google Scholar]
  25. Morgan S. J., Moore M. W., Cacalano G., Ley K. Reduced leukocyte adhesion response and absence of slow leukocyte rolling in interleukin-8 receptor-deficient mice. Microvasc Res. 1997 Sep;54(2):188–191. doi: 10.1006/mvre.1997.2029. [DOI] [PubMed] [Google Scholar]
  26. Norton C. R., Rumberger J. M., Burns D. K., Wolitzky B. A. Characterization of murine E-selectin expression in vitro using novel anti-mouse E-selectin monoclonal antibodies. Biochem Biophys Res Commun. 1993 Aug 31;195(1):250–258. doi: 10.1006/bbrc.1993.2037. [DOI] [PubMed] [Google Scholar]
  27. Nourshargh S., Larkin S. W., Das A., Williams T. J. Interleukin-1-induced leukocyte extravasation across rat mesenteric microvessels is mediated by platelet-activating factor. Blood. 1995 May 1;85(9):2553–2558. [PubMed] [Google Scholar]
  28. Perry M. A., Granger D. N. Role of CD11/CD18 in shear rate-dependent leukocyte-endothelial cell interactions in cat mesenteric venules. J Clin Invest. 1991 May;87(5):1798–1804. doi: 10.1172/JCI115200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pries A. R. A versatile video image analysis system for microcirculatory research. Int J Microcirc Clin Exp. 1988 Nov;7(4):327–345. [PubMed] [Google Scholar]
  30. Scharffetter-Kochanek K., Lu H., Norman K., van Nood N., Munoz F., Grabbe S., McArthur M., Lorenzo I., Kaplan S., Ley K. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med. 1998 Jul 6;188(1):119–131. doi: 10.1084/jem.188.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Springer T. A. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol. 1995;57:827–872. doi: 10.1146/annurev.ph.57.030195.004143. [DOI] [PubMed] [Google Scholar]
  32. Sriramarao P., von Andrian U. H., Butcher E. C., Bourdon M. A., Broide D. H. L-selectin and very late antigen-4 integrin promote eosinophil rolling at physiological shear rates in vivo. J Immunol. 1994 Nov 1;153(9):4238–4246. [PubMed] [Google Scholar]
  33. Weber C., Lu C. F., Casasnovas J. M., Springer T. A. Role of alpha L beta 2 integrin avidity in transendothelial chemotaxis of mononuclear cells. J Immunol. 1997 Oct 15;159(8):3968–3975. [PubMed] [Google Scholar]
  34. Zhao Y., Chien S., Skalak R. A stochastic model of leukocyte rolling. Biophys J. 1995 Oct;69(4):1309–1320. doi: 10.1016/S0006-3495(95)79998-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zimmerman G. A., Prescott S. M., McIntyre T. M. Endothelial cell interactions with granulocytes: tethering and signaling molecules. Immunol Today. 1992 Mar;13(3):93–100. doi: 10.1016/0167-5699(92)90149-2. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES