Endothelial heterogeneity and adhesion molecules N-glycosylation: Implications in leukocyte trafficking in inflammation

Abstract

Inflammation is a major contributing element to a host of diseases with the interaction between leukocytes and the endothelium being key in this process. Much is understood about the nature of the adhesion molecule proteins expressed on any given leukocyte and endothelial cell that modulates adhesive interactions. Although it is appreciated that these proteins are heavily glycosylated, relatively little is known about the roles of these posttranslational modifications and whether they are regulated, and if so how during inflammation. Herein, we suggest that a paucity in this understanding is one major reason for the lack of successful therapies to date for modulating leukocyte-endothelial interactions in human inflammatory disease and discuss developing paradigms of (i) how endothelial adhesion molecule glycosylation (with a focus on N-glycosylation) maybe a critical element in understanding endothelial heterogeneity between different vascular beds and species, (ii) how adhesion molecule N-glycosylation may be under distinct, and as yet, unknown modes of regulation during inflammatory stress to affect the inflammatory response in a vascular bed- and disease-specific manner (analogous to a "zip code" for inflammation) and finally (iii) to underscore the concept that a fuller appreciation of the role of adhesion molecule glycoforms is needed to provide foundations for disease and tissue-specific targeting of inflammation.

The Role of Sialylated Glycans in Human Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1)-mediated Trans Homophilic Interactions and Endothelial Cell Barrier Function

“…More important, however, is the observation that endothelial cell adhesion molecules from different species often differ in both the number and location of functional glycosylation sites. For example, human ICAM-1, vascular cell adhesion molecule, E-selectin, and P-selectin have 8, 6, 9, and 11 N-linked glycans, whereas their murine counterparts express 10, 7, 11, and 12, respectively (47). In the case of PECAM-1, murine PECAM-1 contains seven as opposed to nine N-linked glycosylation sites and is missing the major glycosylation site, Asn-25, in IgD1 that is present at the homophilic binding interface of human PECAM-1 (Fig.…”

Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology

“…Absence of sLex, as seen in patients with SLC35C1 mutations, results in impairment of this process and leukocyte adhesion deficiency type 2 (discussed separately) (15). In addition to sLex, other glycoprotein ligands for the Selectins are important to leukocyte homing and trafficking exist and include GlycCAM1, P-selectin glycoprotein ligand 1 (PSGL1), and α M β 2 integrin (16). …”

Effect of Agmatine on Actin Polymerization Dynamics in Wga-Stimulated Leukocytes Under Diabetes Mellitus in Rats

“…Для того щоб проникнути крізь судинну стін-ку, лейкоцити первинно взаємодіють з ендотелієм, перекочуються по його поверхні, зазнають щільної адгезії, розпластуються і, нарешті, переміщуються крізь або між ендотеліальними клітинами кровоносної судини [11][12][13]. В адгезивних взаємодіях лейкоцитів з ендотеліоцитами безпосередню участь беруть L-, Е-і Р-селектини [14,15].…”