Trends in Molecular Medicine
The role of selectins in inflammation and disease
Section snippets
Selectin ligands
There are many candidate ligands for selectins, but only P-selectin glycoprotein ligand 1 (PSGL-1) has been extensively characterized at the molecular, cellular and functional level (Fig. 2). Knockout mice lacking the gene encoding PSGL-1 3, 4 show delayed neutrophil recruitment and moderate neutrophilia (threefold elevation), similar to that of P-selectin knockout mice 5, 6. In addition to being responsible for ∼90% of P-selectin binding, PSGL-1 is also the most important L-selectin ligand in
Inflammation
In most organs, leukocyte recruitment proceeds in a cascade-like fashion from capture to rolling to a systematic decrease of rolling velocity to firm adhesion and transmigration [10]. The selectins participate in the capture, rolling and slow-rolling steps [11]. In addition, there is evidence that selectin engagement can trigger signaling events in the leukocyte through L-selectin [12] and PSGL-1 [13], and in endothelial cells through E-selectin [14].
Effective neutrophil recruitment requires
Selectin-dependent monocyte functions
Monocytes express functional PSGL-1 and use selectins to leave the vascular system. In models of atherosclerosis, blocking of P-selectin reduces monocyte rolling and adhesion to the arterial endothelium [37]; P-selectin-deficient mice show a reduction in the size of atherosclerotic lesions [38] and decreased neointima formation after arterial injury [39]. The role of E-selectin is less significant, and mice lacking this molecule show only a modest reduction in atherosclerotic lesion size.
Selectin-dependent platelet functions
Activated platelets express P-selectin, which binds PSGL-1 on leukocytes and monocytes (Fig. 3). This interaction is responsible for the recruitment of inflammatory leukocytes to thrombi [40], where they are thought to help organize and resolve the thrombus, although the role of selectins has not been formally tested in models of this process. An additional function of platelet P-selectin is in the recruitment of monocyte-derived microparticles, which are a rich source of the blood-clotting
Selectin functions in the adaptive immune system
Mice lacking L-selectin show a severe defect in the homing of naive T lymphocytes to peripheral lymph nodes, a moderate defect in homing to mesenteric lymph nodes, and a subtle defect in homing to Peyer's patches; cells expressing L-selectin cannot roll on high endothelial venules in lymph nodes, which express L-selectin ligands that are different from PSGL-1 8, 43. Central memory T cells also express L-selectin, and their homing to peripheral lymph nodes might also be impaired in
Organ specificity
Intravital microscopic, cell homing and disease studies all suggest that selectin recruitment differs among organs. For example, neutrophil recruitment to the liver and lung is largely selectin-independent 51, 52, although exceptions exist in some lung models. In general terms, based on the pathologies seen in mice and humans, P- and E-selectin are important in neutrophil recruitment to skin and mucosal membranes, and to kidney, skeletal muscle and heart, but not to liver or to lung after
Use of selectins for targeted delivery and diagnostics
P- and E-selectins are expressed at reasonably high density on the luminal plasma membrane of vascular endothelial cells at sites of inflammation, and are therefore, in principle, suitable targets for the delivery of drugs, plasmids for gene therapy, and imaging contrast agents. Indeed, P-selectin has successfully been targeted by ultrasound contrast agents [57], enabling the selective and specific imaging of inflamed kidney and heart muscle. Antibody conjugates have also been used to deliver
Therapeutic use of selectin inhibitors
Four classes of selectin inhibitors have been developed and tested in preclinical models and some clinical trials. The first developed were carbohydrate-based selectin inhibitors of the sialyl Lewisx type, which inhibit all three selectins at high concentrations. However, their unfavorable pharmacokinetics, low affinity and relatively high production costs made them unsuitable for further development.
Second, antibodies to selectins have been developed and humanized, including antibodies that
Conclusions
Selectins are crucial for the innate immune response, as demonstrated in selectin-deficient and selectin-ligand-deficient patients and in mouse models. Disease treatment using selectin inhibition shows most promise in ischemia–reperfusion-type situations and in skin diseases. However, chronic selectin inhibition will probably produce unfavorable consequences by suppressing the innate immune system. The effects of transient selectin inhibition in well-controlled clinical settings, such as organ
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