Journal of Molecular Medicine

, Volume 90, Issue 4, pp 353–359 | Cite as

Leukocyte integrin activation and deactivation: novel mechanisms of balancing inflammation

  • Alexander ZarbockEmail author
  • Tibor Kempf
  • Kai C. Wollert
  • Dietmar Vestweber


Leukocyte recruitment into tissue forms the basis of immune surveillance and direct immune defense. It proceeds in a cascade-like fashion. The first contact of leukocytes with the endothelium is mediated by selectins and their counter receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several signaling pathways leading to leukocyte adhesion to the endothelium and transmigration through the blood vessel wall into the inflamed tissue. Whereas inflammatory reactions are beneficial and necessary for host defense, they need to be balanced and controlled to prevent harmful consequences and tissue destruction. In this article, we discuss the different signaling pathways that ensure rapid and efficient integrin activation on leukocytes. In addition, we report on a recently identified novel endogenous mechanism that counteracts and balances integrin activation, thereby limiting leukocyte recruitment and the extent of inflammation. Further investigation of this new mechanism may allow providing new approaches for the development of the next generation of anti-inflammatory drugs.


Selectin Chemokin Integrin regulation Signaling GDF-15 



This study is supported by grants from the German Research Foundation (AZ 428/3-1 and AZ 428/6-1 to A.Z.) and the Interdisciplinary Clinical Research Center (IZKF Muenster, Germany, Za2/001/10 to A.Z.).

Disclosure statement

The authors declare no conflict of interest related to this study.


  1. 1.
    Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7:678–689PubMedCrossRefGoogle Scholar
  2. 2.
    Vestweber D (2007) Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol Rev 218:178–196PubMedCrossRefGoogle Scholar
  3. 3.
    McEver RP, Zhu C (2010) Rolling cell adhesion. Annu Rev Cell Dev Biol 26:363–396PubMedCrossRefGoogle Scholar
  4. 4.
    Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedCrossRefGoogle Scholar
  5. 5.
    Abram CL, Lowell CA (2007) Convergence of immunoreceptor and integrin signaling. Immunol Rev 218:29–44PubMedCrossRefGoogle Scholar
  6. 6.
    Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647PubMedCrossRefGoogle Scholar
  7. 7.
    Springer TA (1997) Folding of the N-terminal, ligand-binding region of integrin alpha-subunits into a beta-propeller domain. Proc Natl Acad Sci U S A 94:65–72PubMedCrossRefGoogle Scholar
  8. 8.
    Takagi J, Petre BM, Walz T, Springer TA (2002) Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110:599–611PubMedCrossRefGoogle Scholar
  9. 9.
    Lu CF, Springer TA (1997) The alpha subunit cytoplasmic domain regulates the assembly and adhesiveness of integrin lymphocyte function-associated antigen-1. J Immunol 159:268–278PubMedGoogle Scholar
  10. 10.
    Shimaoka M, Xiao T, Liu JH, Yang Y, Dong Y, Jun CD, McCormack A, Zhang R, Joachimiak A, Takagi J et al (2003) Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 112:99–111PubMedCrossRefGoogle Scholar
  11. 11.
    Rose DM, Alon R, Ginsberg MH (2007) Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev 218:126–134PubMedCrossRefGoogle Scholar
  12. 12.
    Diamond MS, Springer TA (1993) A subpopulation of Mac-1 (CD11b/CD18) molecules mediates neutrophil adhesion to ICAM-1 and fibrinogen. J Cell Biol 120:545–556PubMedCrossRefGoogle Scholar
  13. 13.
    Pasvolsky R, Feigelson SW, Kilic SS, Simon AJ, Tal-Lapidot G, Grabovsky V, Crittenden JR, Amariglio N, Safran M, Graybiel AM et al (2007) A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med 204:1571–1582PubMedGoogle Scholar
  14. 14.
    Zarbock A, Lowell CA, Ley K (2007) Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1. Immunity 26:773–783PubMedCrossRefGoogle Scholar
  15. 15.
    Ding ZM, Babensee JE, Simon SI, Lu H, Perrard JL, Bullard DC, Dai XY, Bromley SK, Dustin ML, Entman ML et al (1999) Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol 163:5029–5038PubMedGoogle Scholar
  16. 16.
    Mayadas TN, Cullere X (2005) Neutrophil beta2 integrins: moderators of life or death decisions. Trends Immunol 26:388–395PubMedCrossRefGoogle Scholar
  17. 17.
    Zarbock A, Polanowska-Grabowska RK, Ley K (2007) Platelet–neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 21:99–111PubMedCrossRefGoogle Scholar
  18. 18.
    Phillipson M, Heit B, Colarusso P, Liu L, Ballantyne CM, Kubes P (2006) Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med 203:2569–2575PubMedCrossRefGoogle Scholar
  19. 19.
    Hyduk SJ, Chan JR, Duffy ST, Chen M, Peterson MD, Waddell TK, Digby GC, Szaszi K, Kapus A, Cybulsky MI (2007) Phospholipase C, calcium, and calmodulin are critical for alpha4beta1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants. Blood 109:176–184PubMedCrossRefGoogle Scholar
  20. 20.
    Kinashi T (2005) Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 5:546–559PubMedCrossRefGoogle Scholar
  21. 21.
    Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, Housman DE, Graybiel AM (2004) CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med 10:982–986PubMedCrossRefGoogle Scholar
  22. 22.
    Stadtmann A, Brinkhaus L, Mueller H, Rossaint J, Bolomini-Vittori M, Bergmeier W, Van Aken H, Wagner DD, Laudanna C, Ley K et al (2011) Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling. Eur J Immunol 41:2074–2085PubMedCrossRefGoogle Scholar
  23. 23.
    Vielkind S, Gallagher-Gambarelli M, Gomez M, Hinton HJ, Cantrell DA (2005) Integrin regulation by RhoA in thymocytes. J Immunol 175:350–357PubMedGoogle Scholar
  24. 24.
    Moser M, Legate KR, Zent R, Fassler R (2009) The tail of integrins, talin, and kindlins. Science 324:895–899PubMedCrossRefGoogle Scholar
  25. 25.
    Zarbock A, Muller H, Kuwano Y, Ley K (2009) PSGL-1-dependent myeloid leukocyte activation. J Leukoc Biol 86:1119–1124PubMedCrossRefGoogle Scholar
  26. 26.
    Miner JJ, Xia L, Yago T, Kappelmayer J, Liu Z, Klopocki AG, Shao B, McDaniel JM, Setiadi H, Schmidtke DW et al (2008) Separable requirements for cytoplasmic domain of PSGL-1 in leukocyte rolling and signaling under flow. Blood 112:2035–2045PubMedCrossRefGoogle Scholar
  27. 27.
    Zarbock A, Abram CL, Hundt M, Altman A, Lowell CA, Ley K (2008) PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling. J Exp Med 205:2339–2347PubMedCrossRefGoogle Scholar
  28. 28.
    Kuwano Y, Spelten O, Zhang H, Ley K, Zarbock A (2010) Rolling on E- or P-selectin induces the extended but not high-affinity conformation of LFA-1 in neutrophils. Blood 116:617–624PubMedCrossRefGoogle Scholar
  29. 29.
    Yago T, Shao B, Miner JJ, Yao L, Klopocki AG, Maeda K, Coggeshall KM, McEver RP (2010) E-selectin engages PSGL-1 and CD44 through a common signaling pathway to induce integrin alphaLbeta2-mediated slow leukocyte rolling. Blood 116:485–494PubMedCrossRefGoogle Scholar
  30. 30.
    Mueller H, Stadtmann A, Van Aken H, Hirsch E, Wang D, Ley K, Zarbock A (2010) Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways. Blood 115:3118–3127PubMedCrossRefGoogle Scholar
  31. 31.
    Mueller KL, Daniels MA, Felthauser A, Kao C, Jameson SC, Shimizu Y (2004) Cutting edge: LFA-1 integrin-dependent T cell adhesion is regulated by both ag specificity and sensitivity. J Immunol 173:2222–2226PubMedGoogle Scholar
  32. 32.
    Mustelin T, Tasken K (2003) Positive and negative regulation of T-cell activation through kinases and phosphatases. Biochem J 371:15–27PubMedCrossRefGoogle Scholar
  33. 33.
    Horejsi V, Zhang W, Schraven B (2004) Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nat Rev Immunol 4:603–616PubMedCrossRefGoogle Scholar
  34. 34.
    Koretzky GA, Abtahian F, Silverman MA (2006) SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6:67–78PubMedCrossRefGoogle Scholar
  35. 35.
    Liu J, Kang H, Raab M, da Silva AJ, Kraeft SK, Rudd CE (1998) FYB (FYN binding protein) serves as a binding partner for lymphoid protein and FYN kinase substrate SKAP55 and a SKAP55-related protein in T cells. Proc Natl Acad Sci U S A 95:8779–8784PubMedCrossRefGoogle Scholar
  36. 36.
    Tybulewicz VL (2005) Vav-family proteins in T-cell signalling. Curr Opin Immunol 17:267–274PubMedCrossRefGoogle Scholar
  37. 37.
    Liu S, Kiosses WB, Rose DM, Slepak M, Salgia R, Griffin JD, Turner CE, Schwartz MA, Ginsberg MH (2002) A fragment of paxillin binds the alpha 4 integrin cytoplasmic domain (tail) and selectively inhibits alpha 4-mediated cell migration. J Biol Chem 277:20887–20894PubMedCrossRefGoogle Scholar
  38. 38.
    Kim M, Carman CV, Springer TA (2003) Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301:1720–1725PubMedCrossRefGoogle Scholar
  39. 39.
    Shamri R, Grabovsky V, Gauguet JM, Feigelson S, Manevich E, Kolanus W, Robinson MK, Staunton DE, von Andrian UH, Alon R (2005) Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat Immunol 6:497–506PubMedCrossRefGoogle Scholar
  40. 40.
    Fumagalli L, Zhang H, Baruzzi A, Lowell CA, Berton G (2007) The SRC family kinases hck and fgr regulate neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine. J Immunol 178:3874–3885PubMedGoogle Scholar
  41. 41.
    Giagulli C, Ottoboni L, Caveggion E, Rossi B, Lowell C, Constantin G, Laudanna C, Berton G (2006) The Src family kinases Hck and Fgr are dispensable for inside-out, chemoattractant-induced signaling regulating beta2 integrin affinity and valency in neutrophils, but are required for beta2 integrin-mediated outside-in signaling involved in sustained adhesion. J Immunol 177:604–611PubMedGoogle Scholar
  42. 42.
    Smith DF, Deem TL, Bruce AC, Reutershan J, Wu D, Ley K (2006) Leukocyte phosphoinositide-3 kinase gamma is required for chemokine-induced, sustained adhesion under flow in vivo. J Leukoc Biol 80:1491–1499PubMedCrossRefGoogle Scholar
  43. 43.
    Gakidis MA, Cullere X, Olson T, Wilsbacher JL, Zhang B, Moores SL, Ley K, Swat W, Mayadas T, Brugge JS (2004) Vav GEFs are required for beta2 integrin-dependent functions of neutrophils. J Cell Biol 166:273–282PubMedCrossRefGoogle Scholar
  44. 44.
    Opal SM, DePalo VA (2000) Anti-inflammatory cytokines. Chest 117:1162–1172PubMedCrossRefGoogle Scholar
  45. 45.
    Kempf T, Zarbock A, Widera C, Butz S, Stadtmann A, Rossaint J, Bolomini-Vittori M, Korf-Klingebiel M, Napp LC, Hansen B et al (2011) GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 17:581–588PubMedCrossRefGoogle Scholar
  46. 46.
    Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K et al (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 94:11514–11519PubMedCrossRefGoogle Scholar
  47. 47.
    Bolomini-Vittori M, Montresor A, Giagulli C, Staunton D, Rossi B, Martinello M, Constantin G, Laudanna C (2009) Regulation of conformer-specific activation of the integrin LFA-1 by a chemokine-triggered Rho signaling module. Nat Immunol 10:185–194PubMedCrossRefGoogle Scholar
  48. 48.
    Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23PubMedCrossRefGoogle Scholar
  49. 49.
    Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S (2003) Natalizumab for active Crohn’s disease. N Engl J Med 348:24–32PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Alexander Zarbock
    • 1
    • 2
    Email author
  • Tibor Kempf
    • 3
  • Kai C. Wollert
    • 3
  • Dietmar Vestweber
    • 2
  1. 1.Department of Anesthesiology and Intensive Care MedicineUniversity of MünsterMünsterGermany
  2. 2.Max-Planck Institute for Molecular BiomedicineMünsterGermany
  3. 3.Molecular and Translational Cardiology, Department of Cardiology and AngiologyHannover Medical SchoolHannoverGermany

Personalised recommendations