What do selectins do

This signal, an inside-out signaling, is then transmitted across the membrane to initiate the conformational or clustering events that are associated with integrin activation. Such activation has been demonstrated in response to several cytokines and chemoattractants. Recombinant human P-selectin immunoglobulin chimera P-sel Ig was prepared as previously described. The endotoxin levels in these reagents were less than 1 endotoxin unit EU per microgram recombinant protein determined by the limulus amoebocyte lysate LAL from Cape Cod.

McEver W. Alexa Fluor —conjugated fibrinogen was prepared using Alexa Fluor protein-labeling kit Molecular Probes. Fresh human blood was collected from healthy, adult volunteers with their informed consent into acid-citrate-dextrose ACD; 38 mM citric acid, 75 mM trisodium citrate, and mM dextrose; ACD final concentration.

The supernatant and interface were removed, and ice-cold PBS was added to restore the original volume. The endotoxin levels in all buffers used were less than 0. Approval for these studies was obtained from the Cleveland Clinic Foundation institutional review board.

Informed consent was provided according to the Declaration of Helsinki. The wells were postcoated with 0. The adherent cells were quantified using a myeloperoxidase MPO assay as described previously. The relative fluorescence intensity was calculated using ImagePro Plus version 4. Freshly isolated human neutrophils were added together with various concentrations of P-sel Ig chimera to fibrinogen-coated wells of tissue culture plates.

As shown in Figure 1A , P-sel Ig chimera enhanced neutrophil adhesion to fibrinogen in a concentration-dependent manner. Over the course of 12 such experiments, the increment in neutrophil adhesion to fibrinogen induced by this concentration of P-sel Ig chimera was increased by about 3-fold although there was considerable variability among donors.

P-selectin increases adhesion of neutrophils to fibrinogen. A Neutrophils were isolated from fresh human blood and added to well tissue culture plates coated with fibrinogen. For the dose-response curve, neutrophils were incubated with indicated concentrations of P-selectin Ig chimera P-sel Ig. After washing, the bound neutrophils were quantified by MPO activities. The numbers of bound neutrophils were calculated according to the standard curves of MPO activities measured using the known amounts of neutrophils.

Control mouse IgG did not enhance cell adhesion Figure 2. PSGL-1 antibodies enhance adhesion of neutrophils to fibrinogen. Other steps of the cell adhesion assay were carried out as described for Figure 1. To exclude that the observed effects of P-sel Ig chimera were due to traces of endotoxin in the reagents, we tested the direct effect of lipopolysaccharide LPS on neutrophil adhesion to fibrinogen. Because native P-selectin, isolated from human platelets and endothelial cells exists as dimeric and oligomeric forms even at the detergent concentrations well above the critical micelle concentration, 39 , 40 such cross-linking of PSGL-1 has clear biologic relevance.

As controls, sP-selectin added with the anti—human IgG antibody failed to stimulate neutrophil adhesion to fibrinogen data not shown. As shown in Figure 3B , the former but not the latter reagent induced cell adhesion. They were then transferred into the wells coated with fibrinogen. Other steps of the cell adhesion assay were same as for Figure 1. Enhanced adhesion to fibrinogen may arise from changes in expression levels or activation of the integrin by either affinity or avidity modulation.

As shown in Figure 4B , fibrinogen bound poorly to nonstimulated neutrophils or to neutrophils stimulated with P-sel Ig chimera. However, when the cells were stimulated with PMA, binding of soluble fibrinogen could be detected.

Furthermore, in examining the adhesion of neutrophils to immobilized fibrinogen, we observed that soluble fibrinogen inhibited the interaction of PMA-stimulated, but not P-sel Ig chimera-stimulated, neutrophils Figure 4C. Results are the representative of 3 independent experiments.

The samples were processed as described in panel A. C Neutrophils were incubated with PMA or P-selectin Ig chimera P-sel Ig in the presence of an increasing concentration of soluble fibrinogen and then transferred to the wells coated with fibrinogen. The image intensity was adjusted to a point where the rim staining was not detectable but the punctuate staining was. With P-sel Ig chimera stimulation, an intermediate staining was observed Figure 5A.

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The cytoplasmic domain of L-selectin interacts with cytoskeletal proteins via alpha-actinin: receptor positioning in microvilli does not require interaction with alpha-actinin. The cytoplasmic tail of L-selectin interacts with members of the Ezrin-Radixin-Moesin ERM family of proteins: cell activation-dependent binding of Moesin but not Ezrin. The interaction of protein kinase C isozymes alpha, iota, and theta with the cytoplasmic domain of L-selectin is modulated by phosphorylation of the receptor.

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P-selectin primes leukocyte integrin activation during inflammation. The various steps of the adhesion cascade. After endothelial activation by cytokines derived from the inflammatory tissue, selectins are expressed on the endothelium.

The interaction between the selectins and their leukocyte ligands will start the rolling process. This will lead to leukocyte activation with increased expression of the integrins which will cause the sticking of the cells to the endothelium. In the last phase, transmigration is mediated mainly by binding of platelet-endothelial cell adhesion molecule-1 PECAM-1 to integrins.

Step 1: Rolling, selectin-dependent. Leukocytes in the circulation must resist tremendous shear forces to stop along the vascular endothelium. Under normal conditions, leukocytes move rapidly and do not adhere to the endothelium. The phenomenon of leukocyte rolling has been known for more than a century, but its molecular basis was delineated only recently. Several studies 25 , 26 showed that, although CD18 MAb block sticking, they do not effect rolling.

MAb to selectins, however, markedly reduced the rolling process in vivo and in vitro Moreover, rolling is dramatically diminished in P-selectin-deficient mice The selectins expressed on the endothelial cells, will bind to the leukocytes through their ligands, mainly SLeX. The presentation of SLeX to E- and P-selectins may be partially mediated by L-selectin which is expressed on the leukocytes.

The rolling phase is transient in part because L-selectin is shed quickly from the leukocytes, and P-selectin on endothelial cells is internalized. Furthermore, at the site of inflammation, free SLeX appears and may compete for binding to the selectins Step 2: Activation, integrin-dependent.

The transition from selectin-mediated adhesion to integrin-mediated adhesion occurs rapidly and involves the activation of the integrin receptors. During rolling, the slowly moving cells are exposed to diverse mediators, which are generated at the site of inflammation and are capable of activating integrins.

These mediators may be secreted as soluble molecules and then bind to adjacent endothelium. Increased adhesive capacity is mediated through both qualitative conformational and quantitative up-regulation of surface expression changes in the integrin receptors. Step 3: Firm adhesion and transendothelial migration, integrins and Ig-like ligands. Activation of integrins results in increased affinity for their Ig-like ligands on the endothelial cells.

This ensures that binding is firm enough to withstand the continuous shear forces in the blood vessels. MAb to both integrins and their Ig-like ligands block the firm adhesion of leukocyte to endothelial cells. CD31 is constitutively expressed on endothelial cells and in contrast to ICAM-1 that is expressed over the entire surface of the endothelial cell, CD31 is located at intercellular junctions Heterotypic interaction between leukocyte and endothelial CD31 was found to be crucial for neutrophil and monocyte diapedesis between endothelial cells.

Studies of genetic deficiency syndromes have provided important insights into the molecular basis and biology of leukocyte emigration.

Both animal and human deficiency syndromes have been described. Animals models. In the cattle model two point mutations were identified within the gene encoding bovine CD These animals suffered from recurrent infections and persistent mature neutrophilia associated with poor growth performance Using methods of homologous recombination in embryonic stem cells, it is possible to generate strains of mice deficient in specific adhesion molecules.

The mutant mice showed an impaired inflammatory response to chemical peritonitis and delayed rejection of cardiac transplants In another model, ICAMdeficient mice were generated. The animals developed normally and had mild granulocytosis.

Deficient mice exhibited abnormalities of inflammatory response, especially in impaired neutrophil emigration In addition, leukocytes from these mice provide negligible stimulation for the mixed lymphocyte reaction. In a recent study using the ICAMdeficient mice, mutant mice were resistant to lethal effects of high dose of endotoxin which correlated with significant decrease in neutrophil infiltration in the liver. As production of various inflammatory cytokines is normal in these mice, the protective effects appear to be related to a diminution in critical leukocyte-endothelial interactions Mice lacking P-selectin develop normally.

However, they exhibit striking leukocytosis, diminished rolling of leukocytes in mesenteric vessels, and delayed recruitment of neutrophils to the peritoneal cavity after experimentally induced peritonitis E-selectin-deficient mice have a milder defect in neutrophil recruitment, and do not have leukocytosis. Still, administration of anti P-selectin MAb to the E-selectin knock-out mice completely blocks neutrophil recruitment, suggesting that in this model some redundancy of function may exist between the two endothelial cell selectins L-selectin knock-out mice were also generated.

These mice had a severe reduction in the number of lymphocytes localized to peripheral lymph nodes and showed significant defects is leukocyte rolling Human LAD syndromes. Currently, two such syndromes are described Table 2 LAD I. This syndrome was described more than 10 y ago and is clinically characterized by severe life-threatening infections, chronic neutrophilia, and impaired wound healing. Delayed separation of the umbilical cord, chronic gingivoperiodontitis, and lack of pus formation complete the clinical picture As a consequence, neutrophils are unable to emigrate from the blood vessels to the tissue, because firm adhesion and transmigration is severely impaired Biopsies from infected lesions in these patients demonstrated inflammatory infiltrates totally devoid of neutrophils.

This histopathologic feature is particularly striking considering that marked peripheral granulocytosis fold higher than normal during episodes of infections is a constant finding Although the defect in neutrophil adherence accounts for the major clinical manifestations, cellular and humoral immune function are impaired in vitro.

However, the in vivo significance of these abnormalities is still unclear. Clinically, LAD I has been divided into two groups, a severe phenotype and a moderate one In the severe form no expression of CD18 can be demonstrated even with leukocyte activation, and the patients suffer from life-threatening infection. The severely affected patients die early in life if definitive therapy is not instituted.

Although antibiotics have some beneficial effect with infectious complications, the definitive approach to the treatment of the severe form of the disease is by bone marrow transplantation. Because the syndrome is a monogenic disorder involving hematopoietic cells, it is obviously an attractive candidate for curative treatment by gene therapy LAD II.

This new adhesion molecule deficiency syndrome was described in It is also characterized by recurrent infections, failure to form pus, gingivitis, and pronounced neutrophilia The severity of the infectious complications resembles that of the moderate type of LAD I. In contrast to LAD I, this syndrome is also characterized by mental and growth retardation, and it exhibits the rare Bombay blood group phenotype LAD II is due to a congenital defect of endogenous fucose metabolism.

This results in an inability to synthesize fucosylated carbohydrate structures, such as the selectin ligand, sialyl Lewis X. Neutrophils from these patients do not bind to E-selectin expressed on cytokine-activated cultured endothelial cells, or to purified E- or P-selectin 48 , and exhibit a marked decrease in migration to skin chambers or skin window in vivo Still, under static conditions the cells adhere normally through integrin-ICAM interactions and can also migrate across endothelial monolayers Compelling evidence in support of the current paradigm of leukocyte-endothelial interaction was obtained by using intravital microscopy to study neutrophil behavior from LAD I and LAD II patients.