Subscribe to RSS
DOI: 10.1055/s-0035-1556588
Cell Adhesion Molecules: Therapeutic Targets for Inhibition of Inflammatory States
Publication History
Publication Date:
31 August 2015 (online)
![](https://www.thieme-connect.de/media/sth/201506/lookinside/thumbnails/10-1055-s-0035-1556588_02222-1.jpg)
Abstract
The diversity of integrins and their complex role in many diseases suggests great potential for this superfamily as drug targets. The initial successes of anti-integrin therapeutics in the treatment of thrombotic disorders suggested that similar anti-integrin agents could be developed for the treatment of inflammatory disorders. While initially a promising strategy, inhibition of the integrins proved to be elusive despite the discovery of highly potent inhibitors. This is due to several reasons, including redundancy among the integrins and the importance of integrins in key physiological systems. Further exploration of the selective role for distinct leukocytic integrins indicated that homing of inflammatory cells to select disease sites depends on a highly regulated expression of discrete integrins and their ligands in limited locations. Selective control of integrin function is also regulated by local chemokines permitting exquisite homing of populations of inflammatory cells to disease sites. A more complete understanding of the regulation of integrin activation in disease states will permit the development of more effective and specific anti-integrin therapeutic agents.
-
References
- 1 Scarborough RM. Development of eptifibatide. Am Heart J 1999; 138 (6 Pt 1): 1093-1104
- 2 Conrad ME, Umbreit JN, Moore EG. Integrin beta3 blockade with abciximab and protection from myocardial ischemic events. JAMA 1998; 279 (3) 195-196
- 3 Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338 (21) 1488-1497
- 4 Cho L, Topol EJ, Balog C , et al. Clinical benefit of glycoprotein IIb/IIIa blockade with Abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation in Percutaneous Transluminal Coronary Angioplasty to Improve Long-Term Outcome with Abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stent. J Am Coll Cardiol 2000; 36 (2) 381-386
- 5 Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69 (1) 11-25
- 6 Shimaoka M, Springer TA. Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discov 2003; 2 (9) 703-716
- 7 Cox D, Aoki T, Seki J, Motoyama Y, Yoshida K. The pharmacology of the integrins. Med Res Rev 1994; 14 (2) 195-228
- 8 Takada Y, Ye X, Simon S. The integrins. Genome Biol 2007; 8 (5) 215
- 9 Alfsen A, Yu H, Magérus-Chatinet A, Schmitt A, Bomsel M. HIV-1-infected blood mononuclear cells form an integrin- and agrin-dependent viral synapse to induce efficient HIV-1 transcytosis across epithelial cell monolayer. Mol Biol Cell 2005; 16 (9) 4267-4279
- 10 Cox D, Brennan M, Moran N. Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov 2010; 9 (10) 804-820
- 11 Todd III RF. The continuing saga of complement receptor type 3 (CR3). J Clin Invest 1996; 98 (1) 1-2
- 12 Mould AP, Askari JA, Humphries MJ. Molecular basis of ligand recognition by integrin alpha 5beta 1. I. Specificity of ligand binding is determined by amino acid sequences in the second and third NH2-terminal repeats of the alpha subunit. J Biol Chem 2000; 275 (27) 20324-20336
- 13 Springer TA. Folding of the N-terminal, ligand-binding region of integrin alpha-subunits into a beta-propeller domain. Proc Natl Acad Sci U S A 1997; 94 (1) 65-72
- 14 Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell 2008; 32 (6) 849-861
- 15 Liddington RC, Ginsberg MH. Integrin activation takes shape. J Cell Biol 2002; 158 (5) 833-839
- 16 Shimaoka M, Salas A, Yang W, Weitz-Schmidt G, Springer TA. Small molecule integrin antagonists that bind to the beta2 subunit I-like domain and activate signals in one direction and block them in the other. Immunity 2003; 19 (3) 391-402
- 17 Mould AP, Travis MA, Barton SJ , et al. Evidence that monoclonal antibodies directed against the integrin beta subunit plexin/semaphorin/integrin domain stimulate function by inducing receptor extension. J Biol Chem 2005; 280 (6) 4238-4246
- 18 Zhu J, Zhu J, Springer TA. Complete integrin headpiece opening in eight steps. J Cell Biol 2013; 201 (7) 1053-1068
- 19 Xiao T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 2004; 432 (7013) 59-67
- 20 Xiong JP, Stehle T, Zhang R , et al. Crystal structure of the extracellular segment of integrin α Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 2002; 296 (5565) 151-155
- 21 Lau TL, Kim C, Ginsberg MH, Ulmer TS. The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling. EMBO J 2009; 28 (9) 1351-1361
- 22 Luo BH, Springer TA, Takagi J. A specific interface between integrin transmembrane helices and affinity for ligand. PLoS Biol 2004; 2 (6) e153
- 23 Wang W, Zhu J, Springer TA, Luo BH. Tests of integrin transmembrane domain homo-oligomerization during integrin ligand binding and signaling. J Biol Chem 2011; 286 (3) 1860-1867
- 24 Yin H, Litvinov RI, Vilaire G , et al. Activation of platelet alphaIIbbeta3 by an exogenous peptide corresponding to the transmembrane domain of alphaIIb. J Biol Chem 2006; 281 (48) 36732-36741
- 25 Stephens G, O'Luanaigh N, Reilly D , et al. A sequence within the cytoplasmic tail of GpIIb independently activates platelet aggregation and thromboxane synthesis. J Biol Chem 1998; 273 (32) 20317-20322
- 26 Sastry SK, Horwitz AF. Integrin cytoplasmic domains: mediators of cytoskeletal linkages and extra- and intracellular initiated transmembrane signaling. Curr Opin Cell Biol 1993; 5 (5) 819-831
- 27 Larkin D, Murphy D, Reilly DF , et al. ICln, a novel integrin alphaIIbbeta3-associated protein, functionally regulates platelet activation. J Biol Chem 2004; 279 (26) 27286-27293
- 28 Brophy TM, Raab M, Daxecker H , et al. RN181, a novel ubiquitin E3 ligase that interacts with the KVGFFKR motif of platelet integrin α(IIb)β3. Biochem Biophys Res Commun 2008; 369 (4) 1088-1093
- 29 Liu S, Thomas SM, Woodside DG , et al. Binding of paxillin to α4 integrins modifies integrin-dependent biological responses. Nature 1999; 402 (6762) 676-681
- 30 Li A, Guo Q, Kim C, Hu W, Ye F. Integrin αII b tail distal of GFFKR participates in inside-out αII b β3 activation. J Thromb Haemost 2014; 12 (7) 1145-1155
- 31 Liu S, Calderwood DA, Ginsberg MH. Integrin cytoplasmic domain-binding proteins. J Cell Sci 2000; 113 (Pt 20): 3563-3571
- 32 Hughes PE, Diaz-Gonzalez F, Leong L , et al. Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J Biol Chem 1996; 271 (12) 6571-6574
- 33 Anthis NJ, Haling JR, Oxley CL , et al. Beta integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation. J Biol Chem 2009; 284 (52) 36700-36710
- 34 Law DA, DeGuzman FR, Heiser P, Ministri-Madrid K, Killeen N, Phillips DR. Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function. Nature 1999; 401 (6755) 808-811
- 35 Blystone SD, Williams MP, Slater SE, Brown EJ. Requirement of integrin beta3 tyrosine 747 for beta3 tyrosine phosphorylation and regulation of alphavbeta3 avidity. J Biol Chem 1997; 272 (45) 28757-28761
- 36 Sakai T, Zhang Q, Fässler R, Mosher DF. Modulation of beta1A integrin functions by tyrosine residues in the beta1 cytoplasmic domain. J Cell Biol 1998; 141 (2) 527-538
- 37 Calderwood DA, Fujioka Y, de Pereda JM , et al. Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc Natl Acad Sci U S A 2003; 100 (5) 2272-2277
- 38 Naik UP, Patel PM, Parise LV. Identification of a novel calcium-binding protein that interacts with the integrin alphaIIb cytoplasmic domain. J Biol Chem 1997; 272 (8) 4651-4654
- 39 Vijayan KV, Liu Y, Li TT, Bray PF. Protein phosphatase 1 associates with the integrin alphaIIb subunit and regulates signaling. J Biol Chem 2004; 279 (32) 33039-33042
- 40 Gushiken FC, Patel V, Liu Y , et al. Protein phosphatase 2A negatively regulates integrin alpha(IIb)beta(3) signaling. J Biol Chem 2008; 283 (19) 12862-12869
- 41 Kato A, Kawamata N, Tamayose K , et al. Ancient ubiquitous protein 1 binds to the conserved membrane-proximal sequence of the cytoplasmic tail of the integrin alpha subunits that plays a crucial role in the inside-out signaling of alpha IIbbeta 3. J Biol Chem 2002; 277 (32) 28934-28941
- 42 Liu QY, Corjay M, Feuerstein GZ, Nambi P. Identification and characterization of triosephosphate isomerase that specifically interacts with the integrin alphaIIb cytoplasmic domain. Biochem Pharmacol 2006; 72 (5) 551-557
- 43 Deshmukh L, Tyukhtenko S, Liu J, Fox JE, Qin J, Vinogradova O. Structural insight into the interaction between platelet integrin alphaIIbbeta3 and cytoskeletal protein skelemin. J Biol Chem 2007; 282 (44) 32349-32356
- 44 Chua GL, Patra AT, Tan SM, Bhattacharjya S. NMR structure of integrin α4 cytosolic tail and its interactions with paxillin. PLoS ONE 2013; 8 (1) e55184
- 45 Calderwood DA. Talin controls integrin activation. Biochem Soc Trans 2004; 32 (Pt3): 434-437
- 46 Wegener KL, Partridge AW, Han J , et al. Structural basis of integrin activation by talin. Cell 2007; 128 (1) 171-182
- 47 Moser M, Legate KR, Zent R, Fässler R. The tail of integrins, talin, and kindlins. Science 2009; 324 (5929) 895-899
- 48 Harburger DS, Bouaouina M, Calderwood DA. Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects. J Biol Chem 2009; 284 (17) 11485-11497
- 49 Fagerholm SC, Lek HS, Morrison VL. Kindlin-3 in the immune system. Am J Clin Exp Immunol 2014; 3 (1) 37-42
- 50 Takala H, Nurminen E, Nurmi SM , et al. Beta2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding. Blood 2008; 112 (5) 1853-1862
- 51 Hart R, Stanley P, Chakravarty P, Hogg N. The kindlin 3 pleckstrin homology domain has an essential role in lymphocyte function-associated antigen 1 (LFA-1) integrin-mediated B cell adhesion and migration. J Biol Chem 2013; 288 (21) 14852-14862
- 52 Gruda R, Brown AC, Grabovsky V , et al. Loss of kindlin-3 alters the threshold for NK cell activation in human leukocyte adhesion deficiency-III. Blood 2012; 120 (19) 3915-3924
- 53 Moretti FA, Moser M, Lyck R , et al. Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells. Proc Natl Acad Sci U S A 2013; 110 (42) 17005-17010
- 54 Morrison VL, MacPherson M, Savinko T, Lek HS, Prescott A, Fagerholm SC. The β2 integrin-kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo. Blood 2013; 122 (8) 1428-1436
- 55 Kasirer-Friede A, Kang J, Kahner B, Ye F, Ginsberg MH, Shattil SJ. ADAP interactions with talin and kindlin promote platelet integrin αIIbβ3 activation and stable fibrinogen binding. Blood 2014; 123 (20) 3156-3165
- 56 Hayward AR, Harvey BA, Leonard J, Greenwood MC, Wood CB, Soothill JF. Delayed separation of the umbilical cord, widespread infections, and defective neutrophil mobility. Lancet 1979; 1 (8126) 1099-1101
- 57 Crowley CA, Curnutte JT, Rosin RE , et al. An inherited abnormality of neutrophil adhesion. Its genetic transmission and its association with a missing protein. N Engl J Med 1980; 302 (21) 1163-1168
- 58 Marlin SD, Morton CC, Anderson DC, Springer TA. LFA-1 immunodeficiency disease. Definition of the genetic defect and chromosomal mapping of alpha and beta subunits of the lymphocyte function-associated antigen 1 (LFA-1) by complementation in hybrid cells. J Exp Med 1986; 164 (3) 855-867
- 59 Etzioni A, Harlan JM, Pollack S, Phillips LM, Gershoni-Baruch R, Paulson JC. Leukocyte adhesion deficiency (LAD) II: a new adhesion defect due to absence of sialyl Lewis X, the ligand for selectins. Immunodeficiency 1993; 4 (1-4) 307-308
- 60 Etzioni A. Defects in the leukocyte adhesion cascade. Clin Rev Allergy Immunol 2010; 38 (1) 54-60
- 61 Larson RS, Hibbs ML, Springer TA. The leukocyte integrin LFA-1 reconstituted by cDNA transfection in a nonhematopoietic cell line is functionally active and not transiently regulated. Cell Regul 1990; 1 (4) 359-367
- 62 Schürpf T, Springer TA. Regulation of integrin affinity on cell surfaces. EMBO J 2011; 30 (23) 4712-4727
- 63 Peroni DG, Djukanović R, Bradding P , et al. Expression of CD44 and integrins in bronchial mucosa of normal and mildly asthmatic subjects. Eur Respir J 1996; 9 (11) 2236-2242
- 64 Zimmerman T, Blanco FJ. Inhibitors targeting the LFA-1/ICAM-1 cell-adhesion interaction: design and mechanism of action. Curr Pharm Des 2008; 14 (22) 2128-2139
- 65 Plow EF, Zhang L. A MAC-1 attack: integrin functions directly challenged in knockout mice. J Clin Invest 1997; 99 (6) 1145-1146
- 66 Solovjov DA, Pluskota E, Plow EF. Distinct roles for the alpha and beta subunits in the functions of integrin alphaMbeta2. J Biol Chem 2005; 280 (2) 1336-1345
- 67 Noti JD, Johnson AK, Dillon JD. The leukocyte integrin gene CD11d is repressed by gut-enriched Kruppel-like factor 4 in myeloid cells. J Biol Chem 2005; 280 (5) 3449-3457
- 68 Noti JD. Expression of the myeloid-specific leukocyte integrin gene CD11d during macrophage foam cell differentiation and exposure to lipoproteins. Int J Mol Med 2002; 10 (6) 721-727
- 69 Miyazaki Y, Bunting M, Stafforini DM , et al. Integrin alphaDbeta2 is dynamically expressed by inflamed macrophages and alters the natural history of lethal systemic infections. J Immunol 2008; 180 (1) 590-600
- 70 Postigo AA, Pulido R, Campanero MR , et al. Differential expression of VLA-4 integrin by resident and peripheral blood B lymphocytes. Acquisition of functionally active alpha 4 beta 1-fibronectin receptors upon B cell activation. Eur J Immunol 1991; 21 (10) 2437-2445
- 71 Millard M, Odde S, Neamati N. Integrin targeted therapeutics. Theranostics 2011; 1: 154-188
- 72 Marazuela M, Postigo AA, Acevedo A, Díaz-González F, Sanchez-Madrid F, de Landázuri MO. Adhesion molecules from the LFA-1/ICAM-1,3 and VLA-4/VCAM-1 pathways on T lymphocytes and vascular endothelium in Graves' and Hashimoto's thyroid glands. Eur J Immunol 1994; 24 (10) 2483-2490
- 73 Laschinger M, Engelhardt B. Interaction of alpha4-integrin with VCAM-1 is involved in adhesion of encephalitogenic T cell blasts to brain endothelium but not in their transendothelial migration in vitro. J Neuroimmunol 2000; 102 (1) 32-43
- 74 Sun H, Liu J, Zheng Y, Pan Y, Zhang K, Chen J. Distinct chemokine signaling regulates integrin ligand specificity to dictate tissue-specific lymphocyte homing. Dev Cell 2014; 30 (1) 61-70
- 75 Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998; 339 (7) 436-443
- 76 Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 1994; 330 (14) 956-961
- 77 Artoni A, Li J, Mitchell B , et al. Integrin β3 regions controlling binding of murine mAb 7E3: implications for the mechanism of integrin alphaIIbbeta3 activation. Proc Natl Acad Sci U S A 2004; 101 (36) 13114-13120
- 78 Stüve O, Bennett JL. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. CNS Drug Rev 2007; 13 (1) 79-95
- 79 Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 2005; 64 (8) 1336-1342
- 80 Fedyk ER, Wyant T, Yang LL , et al. Exclusive antagonism of the α4 β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates. Inflamm Bowel Dis 2012; 18 (11) 2107-2119
- 81 Yao K, Gagnon S, Akhyani N , et al. Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS ONE 2008; 3 (4) e2028
- 82 Bloomgren G, Richman S, Hotermans C , et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366 (20) 1870-1880
- 83 Picarella D, Hurlbut P, Rottman J, Shi X, Butcher E, Ringler DJ. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J Immunol 1997; 158 (5) 2099-2106
- 84 Danese S, Panés J. Development of drugs to target interactions between leukocytes and endothelial cells and treatment algorithms for inflammatory bowel diseases. Gastroenterology 2014; 147 (5) 981-989
- 85 Garnock-Jones KP. Vedolizumab: a review of its use in adult patients with moderately to severely active ulcerative colitis or Crohn's disease. Bio Drugs 2015; 29 (1) 57-67
- 86 Jullien D, Prinz JC, Langley RG , et al. T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva): mechanisms of action. Dermatology 2004; 208 (4) 297-306
- 87 Frampton JE, Plosker GL. Efalizumab: a review of its use in the management of chronic moderate-to-severe plaque psoriasis. Am J Clin Dermatol 2009; 10 (1) 51-72
- 88 Wang LC, Wang IH, Jou JR. Optic neuritis secondary to Angiostrongylus cantonensis infection. Ocul Immunol Inflamm 2006; 14 (3) 189-191
- 89 Vanderslice P, Woodside DG. Integrin antagonists as therapeutics for inflammatory diseases. Expert Opin Investig Drugs 2006; 15 (10) 1235-1255
- 90 Halland N, Blum H, Buning C, Kohlmann M, Lindenschmidt A. Small Macrocycles As Highly Active Integrin α2β1 Antagonists. ACS Med Chem Lett 2014; 5 (2) 193-198
- 91 Grove RA, Shackelford S, Sopper S , et al. Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis. Eur J Neurol 2013; 20 (7) 1032-1042
- 92 Sedgwick JB, Jansen KJ, Kennedy JD, Kita H, Busse WW. Effects of the very late adhesion molecule 4 antagonist WAY103 on human peripheral blood eosinophil vascular cell adhesion molecule 1-dependent functions. J Allergy Clin Immunol 2005; 116 (4) 812-819