STRUCTURE

CD18 is a β chain of the integrin family. It is a transmembrane glycoprotein with a large extracellular portion and a small cytoplasmic tail. The extracellular part contains a conserved region rich in cysteines divided into 4 tandem repeats. In addition, as other β chain integrins, CD18 contains in the extracellular region a plexin-semaphorin-integrin domain, an I-like domain and four I-EGF folds followed by a β-tail domain. ^1-3 Apart from the membrane- bound form, CD18 can also be found in a soluble form.⁴

1. Shi M, Sundramurthy K, Liu B, Tan SM, Law SK, Lescar J. The crystal structure of the plexin-semaphorin-integrin domain/hybrid domain/I-EGF1 segment from the human integrin beta2 subunit at 1.8-A resolution. J Biol Chem. 2005;280:30586-93.

2. Tan SM. The leucocyte β2 (CD18) integrins: the structure, functional regulation and signalling properties. Biosci Rep. 2012;32:241-69.

3. Arnaout MA. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood. 1990;75:1037-50.

4. Evans BJ, McDowall A, Taylor PC, Hogg N, Haskard DO, Landis RC. Shedding of lymphocyte function-associated antigen-1 (LFA-1) in a human inflammatory response. Blood. 2006;107:3593-9.

LIGANDS

Extracellular

It interacts in cis with CD11a, CD11b, CD11c and CD11d. The ligands of the integrins constituted with the combination of CD18 and the corresponding CD11 will be explained in the CD11 section.^1-2

Intracellular associate molecules

Cytohesin-1³, alpha-actinin⁴, filamin⁵, talin⁶, Yes⁵, Lyn⁷, SYK⁸, Rack1 ⁹, radixin¹⁰, PKC¹¹, JAB1¹², FHL2¹³, DOK1¹⁴, Dab¹⁵, calpain ¹⁶ and 14-3-3 proteins.¹⁷

1. Sanchez-Madrid F, Nagy JA, Robbins E, Simon PA, Springer TA: A human leukocyte differentiation antigen family with distinct alpha subunits and a common beta subunit: The lymphocyte function associated antigen (LFA-I), the C2bi complement receptor (OKMl/Mac-I), and the p150,95 molecule. J Exp Med. 1983;158:1785,1983

2. Van der Vieren M, Le Trong H, Wood CL, Moore PF, St John T, Staunton DE, Gallatin WM. A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3. Immunity. 1995;3:683-90.

3. Kolanus W, Nagel W, Schiller B, Zeitlmann L, Godar S, Stockinger H, Seed B. Alpha L beta 2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell. 1996;86:233-42.

4. Pavalko FM, LaRoche SM. Activation of human neutrophils induces an interaction between the integrin beta 2-subunit (CD18) and the actin binding protein alpha-actinin. J Immunol. 1993;151:3795-807.

5. Sharma CP, Ezzell RM, Arnaout MA. Direct interaction of filamin (ABP-280) with the beta 2-integrin subunit CD18. J Immunol. 1995;154:3461-70.

6. Sampath R, Gallagher PJ, Pavalko FM. Cytoskeletal interactions with the leukocyte integrin beta2 cytoplasmic tail. Activation-dependent regulation of associations with talin and alpha-actinin. J Biol Chem. 1998;273:33588-94.

7. Arias-Salgado EG, Lizano S, Shattil SJ, Ginsberg MH. Specification of the direction of adhesive signaling by the integrin beta cytoplasmic domain. J Biol Chem. 2005;280:29699-707.

8. Willeke T, Schymeinsky J, Prange P, Zahler S, Walzog B. A role for Syk-kinase in the control of the binding cycle of the beta2 integrins (CD11/CD18) in human polymorphonuclear neutrophils. J Leukoc Biol. 2003;74:260-9.

9. Liliental J, Chang DD. Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit. J Biol Chem. 1998;273:2379-83.

10. Tang P, Cao C, Xu M, Zhang L. Cytoskeletal protein radixin activates integrin alpha(M)beta(2) by binding to its cytoplasmic tail. FEBS Lett. 2007;581:1103-8.

11. Fagerholm S, Morrice N, Gahmberg CG, Cohen P. Phosphorylation of the cytoplasmic domain of the integrin CD18 chain by protein kinase C isoforms in leukocytes. J Biol Chem. 2002;277:1728-38.

12. Bianchi E, Denti S, Granata A, Bossi G, Geginat J, Villa A, Rogge L, Pardi R. Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity. Nature. 2000;404:617-21.

13. Wixler V, Geerts D, Laplantine E, Westhoff D, Smyth N, Aumailley M, Sonnenberg A, Paulsson M. The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes. J Biol Chem. 2000 27;275:33669-78.

14. Gupta S, Chit JC, Feng C, Bhunia A, Tan SM, Bhattacharjya S. An Alternative Phosphorylation Switch in Integrin β2 (CD18) Tail for Dok1 Binding. Sci Rep. 2015;5:11630.

15. Calderwood DA, Fujioka Y, de Pereda JM, García-Alvarez B, Nakamoto T, Margolis B, McGlade CJ, Liddington RC, Ginsberg MH. 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;100:2272-7.

16. Pfaff M, Du X, Ginsberg MH. Calpain cleavage of integrin beta cytoplasmic domains. FEBS Lett. 1999;460:17-22.

17. Fagerholm SC, Hilden TJ, Nurmi SM, Gahmberg CG. Specific integrin alpha and beta chain phosphorylations regulate LFA-1 activation through affinity-dependent and -independent mechanisms. J Cell Biol. 2005;171:705-15.

CD18 is expressed in all leukocytes in combination with an alpha chain. With CD11d, it is expressed on macrophages, monocytes, neutrophils and eosinophils. With CD11c, it is expressed on monocytes, macrophages, dendritic cells and NK cells. With CD11b, it is expressed on monocytes, macrophages, NK cells, neutrophils and γδ T cells. Last, with CD11a, it is present in all leukocytes.^1-2

1. Tan SM. The leucocyte β2 (CD18) integrins: the structure, functional regulation and signalling properties. Biosci Rep. 2012;32:241-69.

2. Miyazaki Y, Vieira-de-Abreu A, Harris ES, Shah AM, Weyrich AS, Castro-Faria-Neto HC, Zimmerman GA. Integrin αDβ2 (CD11d/CD18) is expressed by human circulating and tissue myeloid leukocytes and mediates inflammatory signaling. PLoS One. 2014;9:e112770.

As part of an integrin, CD18 is involved in adhesion processes, although the precise role depends on the alpha-subunit that is bound to CD18. When combined with CD11a, it participates in the slow-rolling of leukocytes, arrest, diapedesis and lateral migration for their extravasation. ^1-5 Another role is to mediate the formation of the immune synapse.⁶ When combined with CD11b, it is involved in phagocytosis, adhesion, remodeling of the extracellular matrix, cell survival and immune tolerance.^7-13 When combined with CD11c, it plays a role in adhesion, phagocytosis and migration of leukocytes. ^13-14 Last, when bound to CD11d, it regulates cell spreading and inflammatory signalling.¹⁵

1. Zarbock A, Lowell CA, Ley K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1. Immunity. 2007;26:773-83.

2. Lefort CT, Ley K. Neutrophil arrest by LFA-1 activation. Front Immunol. 2012;3:157.

3. Schenkel AR, Mamdouh Z, Muller WA. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol. 2004;5:393-400.

4. Ostermann G, Weber KS, Zernecke A, Schröder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002;3:151-8.

5. Carman CV, Sage PT, Sciuto TE, de la Fuente MA, Geha RS, Ochs HD, Dvorak HF, Dvorak AM, Springer TA. Transcellular diapedesis is initiated by invasive podosomes. Immunity. 2007;26:784-97.

6. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. The immunological synapse: a molecular machine controlling T cell activation. Science. 1999;285:221-7.

7. Graham IL, Gresham HD, Brown EJ. An immobile subset of plasma membrane CD11b/CD18 (Mac-1) is involved in phagocytosis of targets recognized by multiple receptors. J Immunol. 1989;142:2352-8.

8. Ding ZM, Babensee JE, Simon SI, Lu H, Perrard JL, Bullard DC, Dai XY, Bromley SK, Dustin ML, Entman ML, Smith CW, Ballantyne CM. Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol. 1999;163:5029-38.

9. Tan SM. The leucocyte β2 (CD18) integrins: the structure, functional regulation and signalling properties. Biosci Rep. 2012;32:241-69.

10. Mayadas TN, Cullere X. Neutrophil beta2 integrins: moderators of life or death decisions. Trends Immunol. 2005;26:388-95.

11. Han C, Jin J, Xu S, Liu H, Li N, Cao X. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol. 2010;11:734-42.

12. Skoberne M, Somersan S, Almodovar W, Truong T, Petrova K, Henson PM, Bhardwaj N. The apoptotic-cell receptor CR3, but not alphavbeta5, is a regulator of human dendritic-cell immunostimulatory function. Blood. 2006;108:947-55.

13. Keizer GD, Te Velde AA, Schwarting R, Figdor CG, De Vries JE. Role of p150,95 in adhesion, migration, chemotaxis and phagocytosis of human monocytes. Eur J Immunol. 1987;17:1317-22.

14. Myones BL, Dalzell JG, Hogg N, Ross GD. Neutrophil and monocyte cell surface p150,95 has iC3b-receptor (CR4) activity resembling CR3. J Clin Invest. 1988;82:640-51.

15. Miyazaki Y, Vieira-de-Abreu A, Harris ES, Shah AM, Weyrich AS, Castro-Faria-Neto HC, Zimmerman GA. Integrin αDβ2 (CD11d/CD18) is expressed by human circulating and tissue myeloid leukocytes and mediates inflammatory signaling. PLoS One. 2014;9:e112770.

Cell marker

Truncated CD18 is a useful marker for activated myeloid cells.¹

The lack of CD18 expression can be used in the diagnosis of acute promyelocytic leukemia. ² In B cell lymphomas, its expression is associated with survival.³

1. Drbal K, Angelisová P, Hilgert I, Cerný J, Novák P, Horejsí V. A proteolytically truncated form of free CD18, the common chain of leukocyte integrins, as a novel marker of activated myeloid cells. Blood. 2001;98:1561-6.

2. Zhou Y, Jorgensen JL, Wang SA, Ravandi F, Cortes J, Kantarjian HM, Medeiros LJ, Konoplev S. Usefulness of CD11a and CD18 in flow cytometric immunophenotypic analysis for diagnosis of acute promyelocytic leukemia. Am J Clin Pathol. 2012;138:744-50.

3. Erikstein BK, Holte H, Kvaløy S, Andersson KB, Steen HB, Hannisdal E, Smeland EB. Expression of CD18 (integrin beta 2 chain) correlates with prognosis in malignant B cell lymphomas. Br J Haematol. 1993;83:392-8.

Therapeutic

Antibodies against CD18 have largely been studied in the context of ischemia, multiple sclerosis and heart attack. Preclinical studies in those areas displayed promising results. However, when introduced to clinical studies, anti-CD18 antibodies failed completely to achieve the goals of the studies.^1-4

1. Dove A. CD18 trials disappoint again. Nat Biotechnol. 2000;18:817-8.

2. Baran KW, Nguyen M, McKendall GR, Lambrew CT, Dykstra G, Palmeri ST, Gibbons RJ, Borzak S, Sobel BE, Gourlay SG, Rundle AC, Gibson CM, Barron HV; Limitation of Myocardial Infarction Following Thrombolysis in Acute Myocardial Infarction (LIMIT AMI) Study Group. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation. 2001;104:2778-83.

3. Rusnak JM, Kopecky SL, Clements IP, Gibbons RJ, Holland AE, Peterman HS, Martin JS, Saoud JB, Feldman RL, Breisblatt WM, Simons M, Gessler CJ Jr, Yu AS. An anti-CD11/CD18 monoclonal antibody in patients with acute myocardial infarction having percutaneous transluminal coronary angioplasty (the FESTIVAL study). Am J Cardiol. 2001;88:482-7.

4. Faxon DP, Gibbons RJ, Chronos NA, Gurbel PA, Sheehan F; HALT-MI Investigators. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J Am Coll Cardiol. 2002;40:1199-204.