Selectins are essential to cell adhesion molecules mediating the trafficking of leukocytes in immune surveillance and inflammation. They are transmembrane, calcium-dependent lectins that mediate leukocyte rolling on vascular surfaces, which is the first adhesive step during inflammation and immune surveillance. The naming of the selectins is based on the original discovery of their cellular expression, with L standing for leukocytes, E for endothelium, and P for platelets. During the course of interactions between the endothelium and leukocytes, selectins are among the initial adhesion molecules, which mediate the transendothelial migration of leukocytes (Fig.1). Targeting selectins have been proposed for a wide variety of inflammatory disorders including post-ischemic, brain, lung, heart, and skin inflammation, atherosclerosis, and cancer.
Fig.1 Selectin-binding glycopolymers in liver homeostasis and inflammation. (Bartneck, et al., 2017)
In an ovalbumin challenge mouse model of asthma, administration of rPSGL-1 is beneficial by reducing eosinophils and lymphocytes in bronchoalveolar lavage fluid without affecting epithelial changes or airway hyperreactivity. In addition, in a model of ocular allergic disease, sensitized and challenged mice with short ragweed pollen and concurrently treated with soluble rPSGL-1 showed an absence of histological late-phase inflammatory changes of the conjunctiva and a dramatic reduction in the induced eosinophil infiltrate in a ragweed-induced type-1 hypersensitivity reaction. Taken together, these data suggest that inhibition of endothelial selectins and PSGL-1 may represent a therapeutic approach in allergic patients.
P-selectin appears to be a key adhesion receptor mediating leukocyte recruitment into arterial lesions promoting advanced atherosclerosis in apolipoprotein E-deficient mice. Mononuclear cell recruitment was reduced while the atherosclerotic lesions were smaller and less calcified, and the fibrous plaque stage of atherosclerosis was delayed in P-selectin deficient mice. The absence of P-selectin in apoE-/-mice dramatically inhibited neointima formation after arterial injury and reduced the mononuclear migration in the neointima of P-selectin-/- arteries. In addition, other approaches that are in the preclinical phase to be potentially translated into humans showed that transient P-selectin or PSGL-1 blockade with monoclonal antibodies RB 40.34 and 4RA10 respectively at the time of arterial injury significantly limited plaque macrophage content and neointima formation after carotid denudation injury in apolipoprotein E-/- mice. In addition, rPSGL-1 protects against myocardial injury and inflammatory response in the porcine and canine coronary artery balloon occlusion models by inhibiting the inflammatory and thrombotic responses at the site of balloon injury.
Constitutive E-selectin expression on dermal microvascular endothelial cells plays a central role in mediating rolling interactions of human skin-homing T cells in physiological conditions and the pathological accumulation of lymphocytes into the skin. The major E-selectin ligand on human skin-homing T cells is CLA, a specialized glycoform of PSGL-1 defined by the monoclonal antibody HECA-452. Antibodies anti-PSGL-1 or PSGL-1 deficiency block the entrance of Th1, but not Th2, cells into the inflamed area of the skin during DTH (delayed type hypersensitivity) reactions. 4-F-GlcNAc, a putative inhibitor of poly-N-acetyl-lactosamine biosynthesis, lowers HECA-452 expression and selectin binding by inhibiting the poly-N-acetyl-lactosamine elongation and selectin-binding determinants on PSGL-1 O-glycans. Furthermore, 4-F-GlcNAc prevents contact hypersensitivity reactions in mice by inhibiting selectin ligand activity and the capacity of effector T cells to enter antigen-challenged skin.
E-selectin, along with L- or P-selectin, mediates cell tethering and rolling interactions through the recognition of sialo-fucosylated Lewis Carbohydrates expressed on structurally diverse protein-lipid ligands on circulating leukocytes or Tumor cells. Major advances in understanding the role of E-selectin in inflammation and cancer have been advanced by experiments assaying E-selectin-mediated rolling of leukocytes and tumor cells under hydrodynamic shear flow, by clinical models of E-selectin-dependent inflammation, by mice deficient in E-selectin and by mice deficient in glycosyltransferases that regulate the binding activity of E-selectin ligands. It is proved that E-selectin and its ligands may facilitate leukocyte or tumor cell recruitment in inflammatory and metastatic settings. Antagonists that target cellular interactions with E-selectin and other members of the selectin family, including neutralizing monoclonal antibodies, competitive ligand inhibitors, Glycoprotein or metabolic carbohydrate mimetics, exemplify a growing arsenal of potentially effective therapeutics in controlling inflammation and the metastatic behavior of cancer.
The role of selectin and related ligands in a number of disease states has led to the design of a variety of small molecule selectin inhibitors and biologic selectin inhibitors to target these interactions.
Small molecule selectin inhibitors have good prospects for treating human diseases. CD BioGlyco provides customized small molecule selectin inhibitors synthesis according to our client’s detailed requirements.
In conclusion, antagonists of the selectin family, such as glycoprotein holds concrete promise for the therapy of several diseases. CD BioGlyco has a strong team of experts with experience in Glycoproteomics analysis. Our professional researchers provide a large number of accurate analysis services according to customers' needs. We hope to start the exploration of glycobiology with you. If you are interested in our services, please feel free to contact us for more detailed information.