Selectins in Biology and Human Disease: Opportunity in E-selectin Antagonism

Overview

Journal Cureus

Specialty Biomedical Engineering

Date 2024 Jul 10

PMID 38983984

Authors

John M Peterson

Theodore A Smith

Edwin P Rock

John L Magnani

Affiliations

Soon will be listed here.

Abstract

Selectins are cell adhesion proteins discovered in the 1980s. As C-type lectins, selectins contain an essential calcium ion in the ligand-binding pocket and recognize the isomeric tetrasaccharides sialyl Lewis (sLe) and sialyl Lewis (sLe). Three selectins, E-selectin, P-selectin, and L-selectin, play distinct, complementary roles in inflammation, hematopoiesis, and tumor biology. They have been implicated in the pathology of diverse inflammatory disorders, and several selectin antagonists have been tested clinically. E-selectin plays a unique role in leukocyte activation, making it an attractive target for intervention, for example, in sickle cell disease (SCD). This review summarizes selectin biology and pathology, structure and ligand binding, and selectin antagonists that have reached clinical testing with an emphasis on E-selectin.

Citing Articles

Vascular Cell Adhesion Molecule 1 and E-Selectin as Potential Cardiovascular Risk Biomarkers in Psoriasis.

Machon N, Zdanowska N, Klimek-Trojan P, Owczarczyk-Saczonek A Int J Mol Sci. 2025; 26(2).

PMID: 39859506 PMC: 11765541. DOI: 10.3390/ijms26020792.

References

Ramphal J, Hiroshige M, Lou B, Gaudino J, Hayashi M, Chen S . Ligand interactions with E-selectin. Identification of a new binding site for recognition of N-acyl aromatic glucosamine substituents of sialyl Lewis X. J Med Chem. 1996; 39(7):1357-60. DOI: 10.1021/jm9600611. View

Dean R, Harkema J, Dixon R, Kogan T . Small-molecule selectin inhibitor protects against liver inflammatory response after ischemia and reperfusion. J Am Coll Surg. 1997; 185(4):365-72. View

Ley K, Tedder T, Kansas G . L-selectin can mediate leukocyte rolling in untreated mesenteric venules in vivo independent of E- or P-selectin. Blood. 1993; 82(5):1632-8. View

Bhushan M, Bleiker T, Ballsdon A, Allen M, Sopwith M, Robinson M . Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial. Br J Dermatol. 2002; 146(5):824-31. DOI: 10.1046/j.1365-2133.2002.04743.x. View

Mondal N, Buffone Jr A, Neelamegham S . Distinct glycosyltransferases synthesize E-selectin ligands in human vs. mouse leukocytes. Cell Adh Migr. 2013; 7(3):288-92. PMC: 3711995. DOI: 10.4161/cam.24714. View

Hamblin A, Shakoor Z, Kapahi P, Haskard D . Circulating adhesion molecules in sarcoidosis. Clin Exp Immunol. 1994; 96(2):335-8. PMC: 1534875. DOI: 10.1111/j.1365-2249.1994.tb06563.x. View

Buffone Jr A, Mondal N, Gupta R, McHugh K, Lau J, Neelamegham S . Silencing α1,3-fucosyltransferases in human leukocytes reveals a role for FUT9 enzyme during E-selectin-mediated cell adhesion. J Biol Chem. 2012; 288(3):1620-33. PMC: 3548472. DOI: 10.1074/jbc.M112.400929. View

Ferri C, Desideri G, Valenti M, Bellini C, Pasin M, Santucci A . Early upregulation of endothelial adhesion molecules in obese hypertensive men. Hypertension. 1999; 34(4 Pt 1):568-73. DOI: 10.1161/01.hyp.34.4.568. View

Preston R, Jakob R, Binder F, Sager C, Ernst B, Maier T . E-selectin ligand complexes adopt an extended high-affinity conformation. J Mol Cell Biol. 2015; 8(1):62-72. PMC: 4710209. DOI: 10.1093/jmcb/mjv046. View

10.

Buerke M, Weyrich A, Zheng Z, Gaeta F, Forrest M, Lefer A . Sialyl Lewisx-containing oligosaccharide attenuates myocardial reperfusion injury in cats. J Clin Invest. 1994; 93(3):1140-8. PMC: 294061. DOI: 10.1172/JCI117066. View

11.

Japp A, Chelliah R, Tattersall L, Lang N, Meng X, Weisel K . Effect of PSI-697, a novel P-selectin inhibitor, on platelet-monocyte aggregate formation in humans. J Am Heart Assoc. 2013; 2(1):e006007. PMC: 3603266. DOI: 10.1161/JAHA.112.006007. View

12.

Mayadas T, Johnson R, Rayburn H, Hynes R, Wagner D . Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell. 1993; 74(3):541-54. DOI: 10.1016/0092-8674(93)80055-j. View

13.

Song M, Graubard B, Rabkin C, Engels E . Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Sci Rep. 2021; 11(1):464. PMC: 7801737. DOI: 10.1038/s41598-020-79431-7. View

14.

Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, Hennerici M . Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke. 1995; 26(8):1361-4. DOI: 10.1161/01.str.26.8.1361. View

15.

Dominguez-Jimenez C, Carretero J, Sabando P, Gonzalez-Alvaro I, Sanchez-Madrid F, Diaz-Gonzalez F . Down-regulation of L-selectin expression in neutrophils by nonsteroidal anti-inflammatory drugs: role of intracellular ATP concentration. Blood. 2000; 96(10):3592-600. View

16.

Sperandio M, Smith M, Forlow S, Olson T, Xia L, McEver R . P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules. J Exp Med. 2003; 197(10):1355-63. PMC: 2193782. DOI: 10.1084/jem.20021854. View

17.

Eriksson E, Xie X, Werr J, Thoren P, Lindbom L . Importance of primary capture and L-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J Exp Med. 2001; 194(2):205-18. PMC: 2193449. DOI: 10.1084/jem.194.2.205. View

18.

Culmer D, Dunbar M, Hawley A, Sood S, Sigler R, Henke P . E-selectin inhibition with GMI-1271 decreases venous thrombosis without profoundly affecting tail vein bleeding in a mouse model. Thromb Haemost. 2017; 117(6):1171-1181. DOI: 10.1160/TH16-04-0323. View

19.

McEver R . Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res. 2015; 107(3):331-9. PMC: 4592324. DOI: 10.1093/cvr/cvv154. View

20.

Suefuji H, Ogawa H, Yasue H, Sakamoto T, Miyao Y, Kaikita K . Increased plasma level of soluble E-selectin in acute myocardial infarction. Am Heart J. 2000; 140(2):243-8. DOI: 10.1067/mhj.2000.107544. View