Reversible interactions of glycoconjugates on leukocytes with P- and E-selectin on endothelial cells mediate tethering and rolling of leukocytes in inflamed vascular beds, the first step in their recruitment to sites of injury. Although selectin ligands on hematopoietic precursors have been identified, here we review evidence that PSGL-1, CD44, and ESL-1 on mature leukocytes are physiologic glycoprotein ligands for endothelial selectins. Each ligand has specialized adhesive functions during tethering and rolling. Furthermore, PSGL-1 and CD44 induce signals that activate the β2 integrin LFA-1 and promote slow rolling, whereas ESL-1 induces signals that activate the β2 integrin Mac-1 in adherent neutrophils. We also review evidence for glycolipids, CD43, L-selectin, and other glycoconjugates as potential physiologic ligands for endothelial selectins on neutrophils or lymphocytes. Although the physiologic characterization of these ligands has been obtained in mice, we also note reported similarities and differences with human selectin ligands.

The selectins mediate adhesion of hematopoietic cells to vascular surfaces and to each other.1  These interactions are important for host defense, hematopoiesis, immune cell surveillance, hemostasis, and inflammation. Each of the 3 selectins is a type I transmembrane protein with an N-terminal C-type lectin domain, an epidermal growth factor-like domain, a series of consensus repeats, a transmembrane domain, and a short cytoplasmic tail. L-selectin is constitutively expressed on most leukocytes. P-selectin is rapidly mobilized from secretory granules to the plasma membranes of platelets and endothelial cells on stimulation. E-selectin expression on endothelial cells is regulated at the transcriptional level by inflammatory mediators, such as tumor necrosis factor-α.

The rolling cell adhesion mediated by selectins is a dynamic process that requires rapid formation and breakage of bonds under flow.2  Rolling enables cells to receive signals that activate integrins, another class of adhesion receptors, which cause the cells to roll slower and to arrest.3  Here we discuss how leukocytes, particularly neutrophils, interact with endothelial selectins during inflammation. We review evidence that surprisingly few neutrophil glycoproteins are physiologic selectin ligands, defined by their ability to mediate rolling adhesion. Rolling can be studied with flow chambers in vitro or ex vivo and in transparent tissues or by epifluorescence in vivo.

The selectins are Ca2+-dependent lectins. The minimal glycan determinant for selectin binding is sialyl Lewis x (sLex; NeuAcα2,3Galβ1,4[Fucα1,3]GlcNAcβ1-R).1  The fucose moiety of sLex expressed on selectin ligands forms critical interactions with the Ca2+-coordination site on the lectin domain of selectins.2  Leukocytes from mice lacking the 2 α1,3-fucosyltransferases that add fucose to form sLex on hematopoietic cells cannot roll on P- and E-selectin.4  Because sLex can potentially cap N- and O-glycans on many proteins and also glycans on lipids, neutrophils might display many selectin ligands. However, α1,3-fucosylation occurs at limited sites on some proteins on human myeloid cells,5  and there is very little α1,3-fucosylation on murine myeloid cells.6  A subset of these glycoproteins might cluster sLex-capped glycans to increase avidity. As described in the next section, P-selectin binds with higher affinity to an N-terminal region of P-selectin glycoprotein ligand-1 (PSGL-1) through cooperative interactions with sulfated tyrosines and other amino acids and with an adjacent sLex-capped O-glycan. However, the affinity or avidity of a glycoprotein for a selectin in solution may not predict physiologic relevance. During rolling, selectins interact with their ligands under 2-dimensional conditions where force regulates off-rates.2  Rolling of a selectin-expressing cell on an isolated glycoprotein does not prove the latter's function in the context of the complex topography of the leukocyte surface (Figure 1A). Factors, such as the number of molecules per cell, molecular length, dimerization or oligomerization, clustering in lipid rafts or microvilli, or cytoskeletal anchorage, may be crucial determinants of function.2  Therefore, the physiologic roles of P- and E-selectin ligands require confirmation in primary leukocytes.

Figure 1

Topography and signaling pathways triggered by selectin ligands in neutrophils. (A) Topography of selectin ligands on neutrophils. Based on biochemical and electron microscopic evidence, PSGL-1 is thought to be concentrated in lipid rafts on the tips of microvilli.13  Electron microscopy places (some of) ESL-1 on microvilli, but not necessarily the tips,69  whereas CD44 is concentrated in the valleys between microvilli.86  LFA-1 and Mac-1 are thought to be mostly on the cell body. (B) Signaling pathways of selectin ligands in neutrophils. Engagement of PSGL-1 by P-selectin or E-selectin or engagement of CD44 by E-selectin induces activation of the SFKs Fgr, Hck, and Lyn.40,82  The activated SFKs phosphorylate the ITAM domains of DAP-12 and FcRγ, enabling them to recruit spleen tyrosine kinase Syk.82  Knocking out Fgr or knocking out both Hck and Lyn blocks this signaling pathway.40,82  Direct physical association between PSGL-1, CD44, and the SFKs has not been demonstrated. Syk activity is needed to activate Bruton tyrosine kinase (Btk), which leads to phospholipase C-γ2 (PLCγ2) activation, providing diacylglycerol (DAG) for the activation of CalDAG-GEFI, an exchange factor for the small G protein Rap-1.84  Rap-1 drives LFA-1 extension through other signaling intermediates (not shown). Engagement of ESL-1 by E-selectin has been shown to activate Mac-1,85  but the signaling pathway is unknown.

Figure 1

Topography and signaling pathways triggered by selectin ligands in neutrophils. (A) Topography of selectin ligands on neutrophils. Based on biochemical and electron microscopic evidence, PSGL-1 is thought to be concentrated in lipid rafts on the tips of microvilli.13  Electron microscopy places (some of) ESL-1 on microvilli, but not necessarily the tips,69  whereas CD44 is concentrated in the valleys between microvilli.86  LFA-1 and Mac-1 are thought to be mostly on the cell body. (B) Signaling pathways of selectin ligands in neutrophils. Engagement of PSGL-1 by P-selectin or E-selectin or engagement of CD44 by E-selectin induces activation of the SFKs Fgr, Hck, and Lyn.40,82  The activated SFKs phosphorylate the ITAM domains of DAP-12 and FcRγ, enabling them to recruit spleen tyrosine kinase Syk.82  Knocking out Fgr or knocking out both Hck and Lyn blocks this signaling pathway.40,82  Direct physical association between PSGL-1, CD44, and the SFKs has not been demonstrated. Syk activity is needed to activate Bruton tyrosine kinase (Btk), which leads to phospholipase C-γ2 (PLCγ2) activation, providing diacylglycerol (DAG) for the activation of CalDAG-GEFI, an exchange factor for the small G protein Rap-1.84  Rap-1 drives LFA-1 extension through other signaling intermediates (not shown). Engagement of ESL-1 by E-selectin has been shown to activate Mac-1,85  but the signaling pathway is unknown.

Close modal

Each approach to identify physiologic selectin ligands on a leukocyte has strengths and limitations. Gene knockout or gene silencing (mRNA knockdown) in mice allows assessment of ligand activity under physiologic conditions, but loss of a glycoprotein might impair rolling through an indirect effect on cellular function rather than by eliminating a key selectin ligand. Definitive identification of a glycoprotein as a selectin ligand should ideally meet several criteria, including: (1) the capacity to support rolling of selectin-bearing cells or beads on isolated ligand; (2) gene depletion or silencing must impair selectin-mediated functions on intact cells in vitro and in vivo (eg, rolling or signaling); and (3) monoclonal antibodies (mAbs) against a specific glycoprotein must also impair selectin-mediated functions. To date, only mAbs to the unique N-terminal P-selectin-binding region of PSGL-1 fulfill the third requirement.1,2  Importantly, mAbs to glycoproteins that reproducibly block binding to E-selectin have not been described. This has significantly hindered testing of physiologic functions of candidate E-selectin ligands on primary human leukocytes, where gene knockout and gene silencing methods are less feasible. In mice, as we discuss in “Additional ligands for E-selectin,” the functional redundancy of E-selectin ligands has required simultaneous deletion of more than one glycoprotein to unmask their functions. Even when all 3 of the aforementioned conditions are met, the ability of mAb or knockout/knockdown approaches to abrogate leukocyte rolling on a selectin may not definitively identify all glycoprotein ligands. Other glycoproteins might be necessary but not sufficient without the targeted glycoproteins.

Despite these challenges, significant progress has been made in identifying physiologic selectin ligands on leukocytes that mediate not only rolling but also signaling, thus enabling integrins to stabilize interactions with endothelial cells and other blood cells. These advances offer the opportunity to identify new physiologic contributions of selectins and their ligands to homeostasis and disease. Here we review the evidence that 3 glycoproteins act as physiologic ligands for P- and/or E-selectin on mouse neutrophils, describe the specialized roles of each ligand for neutrophil recruitment during inflammation, discuss limitations of current data and some controversies, note other leukocyte glycoproteins and glycolipids that might be physiologic ligands, and suggest avenues for future research. The contributions of selectin ligands on hematopoietic precursors to in vivo trafficking are less well characterized and will not be discussed here.

PSGL-1

PSGL-1 is a major selectin ligand on leukocytes. PSGL-1 binds to P-selectin,7  E-selectin,8,9  and L-selectin10  under flow conditions. It is the predominant physiologic ligand for P-selectin and L-selectin on leukocytes, and it cooperates with additional ligands to mediate leukocyte rolling on E-selectin. In addition to mediating leukocyte tethering and rolling, it transduces signals into rolling leukocytes and into leukocytes decorated with platelets.11 

PSGL-1 is a type I membrane protein that is preferentially located in lipid rafts12  on the tips of microvilli13  (Figure 1A). It is expressed as a disulfide-linked homodimer; each subunit consists of an extracellular, transmembrane, and cytoplasmic domain14,15  (Figure 1B). The extracellular domain of PSGL-1 is rich in prolines, serines, and threonines, most of which are located in a series of decameric repeats (14-16 in humans and 15 in mice).16,17  Posttranslational modifications of PSGL-1 are important for optimal selectin binding.15  Protein O-glycosylation is initiated by a polypeptide N-acetylgalactosamine transferase (ppGalNAcT) that adds GalNAc to serine and threonine residues. Leukocytes from mice lacking the glycosyltransferase ppGalNAcT-1 roll poorly on P- and E-selectin in vitro.18  To bind to P-selectin, PSGL-1 requires an α2,3-sialylated and α1,3-fucosylated core 2 O-glycan attached to a specific N-terminal threonine.15  Three core 2 β1,6-N-acetylglucosaminyltransferase enzymes (C2GnT) transfer GlcNAc to the Galβ1,3GalNAc core 1 structure.19  Studies with knockout mice have established the contribution of C2GnT1 to leukocyte interactions with all 3 selectins.20-24  C2GnT1 is required for the trafficking of neutrophils and activated T cells to sites of inflammation.20,22  Sulfation of tyrosine residues near the N-terminus optimizes the binding of PSGL-1 to P-selectin.15,25  To bind to E-selectin, PSGL-1 requires core 2 α1,3-fucosylated and α2,3-sialylated O-glycans but not tyrosine sulfation.15,26  Interactions of chemokines with the N-terminal domain of PSGL-1 may enhance recruitment of specific leukocyte subsets into inflamed or secondary lymphoid tissues.27,28  Interestingly, PSGL-1 glycosylation, which promotes selectin binding, negatively affects chemokine binding.28 

The sequences of the transmembrane and cytoplasmic domains of PSGL-1 are highly conserved. In the endoplasmic reticulum, cooperative interactions between transmembrane domains and between cytoplasmic domains facilitate the formation of PSGL-1 dimers.29,30  Each noncovalent dimer is then stabilized by a single juxtamembrane disulfide bond. An export signal in the cytoplasmic domain promotes transfer of PSGL-1 from the endoplasmic reticulum to the Golgi apparatus, where O-glycans are added en route to the cell surface.30  The cytoplasmic tail of PSGL-1 consists of 67 amino acids in mice and 69 amino acids in humans and may interact with different proteins.11  In vitro, the cytoplasmic domain binds to ezrin/radixin/moesin (ERM) proteins, which in turn interact with actin filaments.31,32  Because both ERM proteins and PSGL-1 move to the uropod on polarization, the PSGL-1-ERM interaction might play a role in later steps of the leukocyte adhesion cascade, such as intravascular crawling or transendothelial migration. Nef-associated factor 1 (Naf-1) forms a constitutive complex with the juxtamembrane region of the cytoplasmic tail of PSGL-1.33  The PSGL-1 tail also binds to selectin ligand interactor cytoplasmic-1 (human ortholog of the mouse sorting nexin 20), which binds phosphoinositides and targets PSGL-1 to endosomes in transfected cells. However, selectin ligand interactor cytoplasmic-1 does not participate in PSGL-1-mediated leukocyte adhesion and signaling in vivo.34 

mAbs to the N-terminal region of human or murine PSGL-1 block P- and L-selectin binding and abolish leukocyte rolling on L-selectin and P-selectin in vivo.7,10,35,36  L- and P- selectin bind to the same or closely overlapping sites near the N-terminus of PSGL-1, whereas E-selectin appears to bind to at least one more site.15  In vivo, PSGL-1-deficient leukocytes have markedly impaired tethering to and rolling on P-selectin.37  They tether less well to E-selectin, but those that tether roll with normal velocities.8,38-40  These observations confirmed that PSGL-1 is the predominant ligand for P-selectin. They also demonstrated that PSGL-1, albeit an important E-selectin ligand, must cooperate with other physiologic ligands for E-selectin, as we discuss in the following 2 sections. In the absence of an inflammatory or infectious challenge, the phenotype of PSGL-1-deficient (Selplg−/−) mice is remarkably mild.8,37 

CD44

CD44 is a class I transmembrane glycoprotein that is expressed on most vertebrate cells, including hematopoietic stem cells, monocytes, neutrophils, lymphocytes, and endothelial cells. CD44 is involved in many cellular processes, including growth, survival, differentiation, and motility. A glycoform of CD44 isolated from human, but not murine, hematopoietic progenitors binds to L- and E-selectin in vitro. This glycoform has been termed hematopoietic cell E-/L-selectin ligand.41,42  Whether hematopoietic cell E-/L-selectin ligand functions as a selectin ligand on intact primary cells in vitro or in vivo has not been established. CD44 on neutrophils and some lymphocytes is a physiologic E-selectin ligand, suggesting cell-specific posttranslational modifications of CD44.39,43  The binding activity of neutrophil-derived CD44 requires its decoration by sialylated, α1,3-fucosylated, N-linked glycans.39  Altered glycosylation of CD44 proteins may account for pathologic conditions. For example, CD44 is hypofucosylated in neutrophils from patients with leukocyte adhesion deficiency type II syndrome.39 

CD44, although encoded by a single gene, has more than 40 isoforms.44  The heterogeneity results from posttranslational modifications, such as sulfation and glycosylation as well as alternative splicing. Cells can simultaneously express multiple CD44 isoforms. The expression profile of the isoforms is dependent on the type of tissue and differentiation stage.45,46  The “standard” form of CD44 is composed of an extracellular amino-terminal globular protein domain, a stem structure, a transmembrane region, and a cytoplasmic tail. Hematopoietic cells express this standard form (Figure 1B), but glycosylation of the standard form varies as cells differentiate.

The N-terminal globular domain of CD44 has motifs that function as docking sites for several components of the extracellular matrix (eg, hyaluronan, collagen, laminin, fibronectin, and glycosaminoglycans).47,48  Binding of hyaluronan by CD44 is tightly regulated by posttranslational modifications.49-51  Physiologic stimuli can alter these modifications, resulting in the induction of hyaluronan binding.50,52 

The stem structure (46 amino acids) links the amino-terminal globular domain to the transmembrane domain, which consists of 23 hydrophobic amino acids and a cysteine residue. The transmembrane domain may be responsible for the association of CD44 proteins with lipid rafts.53  Although the cytoplasmic tail of CD44 has no intrinsic catalytic activity, it interacts with several intracellular signaling molecules, including Src family kinases (SFKs), Rho GTPase, Rho kinase, and protein kinase C.54  It is not known whether these interactions are direct or indirect or whether they have functional impact in leukocytes.

CD44-deficient mice develop normally but have altered immune responses.55  CD44 has hyaluronan-dependent and -independent functions. Intravital microscopy has documented CD44-dependent rolling of T-cell subsets on hyaluronan in vivo.56-58  In vivo experiments also demonstrated that CD44 and hyaluronan are required for T-cell recruitment into the inflamed peritoneal cavity.59  CD44 and hyaluronan may enhance neutrophil recruitment to sites of inflammation.60-62  However, neutrophils do not tether to and roll on hyaluronan,61,62  and this agrees with the normal recruitment of neutrophils to the inflamed peritoneal cavity of Cd44−/− mice.39  In contrast, sequestration of neutrophils within liver sinusoids has been shown to be CD44- and hyaluronan-dependent.62  CD44-deficient neutrophils show reduced adhesion to the inflamed endothelium and subsequently increased rolling flux60,63  and increased rolling velocities,39  suggesting that CD44 is important for adhesion and/or sequestration.

T-lymphocytes require CD44 for integrin α4β1-mediated firm adhesion to the endothelium; this function requires the cytoplasmic tail of CD44.64,65  CD44-dependent rolling of T-helper (Th1) and Th2 CD4 lymphocytes has been observed in a mouse model of tumor necrosis factor-α–induced inflammation.56  CD44 extracted from Th1 lymphocytes binds to soluble E-selectin in vitro and cooperates with PSGL-1 in vivo by controlling rolling velocities and promoting firm arrest.43  Competitive recruitment assays demonstrated that T cells lacking both CD44 and PSGL-1 have more severe defects in migration to inflamed sites than T cells lacking only PSGL-1.43 

ESL-1

Deleting PSGL-1 and CD44 in murine neutrophils strongly reduces but does not eliminate rolling on E-selectin in vitro or in vivo.39  A third key glycoprotein ligand for E-selectin on murine neutrophils is E-selectin ligand-1 (ESL-1). ESL-1 (also called MGF-160 or CFR-1, encoded by the gene Glg1) is a type I transmembrane protein. It consists of 1148 amino acids with 16 conserved cysteine-rich repeats and 5 potential N-glycosylation sites in the extracellular domain, a 21-residue transmembrane domain, and a short 13-residue cytoplasmic tail66,67  (Figure 1B). Although ESL-1 primarily localizes in the Golgi apparatus, a minor portion of ESL-1 is also exported to the plasma membrane, perhaps because of differential processing of the C-terminal domain.68,69  ESL-1 is expressed in many cell types,70  but selectin-binding activity has only been demonstrated in myeloid cells and human metastatic prostate cancer cells.71-73  Available antibodies to ESL-1 do not detect the protein on leukocyte surfaces by flow cytometry. Biotinylation strategies have demonstrated surface expression of ESL-1 on murine neutrophils69  and lymphocytes (A.H., unpublished data, January 2007), but not on human neutrophils and lymphocytes (D. Vestweber, oral communication, Max-Planck Institute for Molecular Medicine, Münster, Germany, August 2011). Although we focus here on its role as a selectin ligand, ESL-1 may exert pleiotropic effects. It functions as a receptor for several members of the fibroblast growth factor family,70,74  and it modulates intracellular processing and secretion of TGF-β.75  Consequently, mice deficient in ESL-1 show growth retardation and skeletal dysplasia.70,75 

The first evidence that ESL-1 could bind E-selectin was obtained by applying myeloid cell lysates to E-selectin affinity columns.73  ESL-1 requires appropriate modifications of N-glycans to bind to E-selectin,67,72,73  whereas O-glycosylation of the glycoprotein has not been described. As with all other selectin ligands, α1,3 fucosylation of ESL-1 is required for interactions with E-selectin. Neutrophils appear to use fucosyltransferase IV to modify ESL-1 and fucosyltransferase VII to modify PSGL-1.76  Although biochemical and cell-based interactions of ESL-1 with E-selectin were documented many years ago,67  a physiologic role for ESL-1 in mediating rolling of murine leukocytes on E-selectin under flow was only recently documented.

Knockdown of ESL-1 by a short hairpin RNA strategy demonstrated that binding of a recombinant soluble form of E-selectin is mildly reduced when ESL-1 alone is absent but is abrogated when both PSGL-1 and ESL-1 are absent.38  Intravital studies of leukocyte rolling in venules of inflamed tissues further showed that leukocyte tethering requires the combined presence of PSGL-1 and ESL-1, where PSGL-1 interacts with both P- and E-selectin and ESL-1 interacts only with E-selectin.

Binding of selectins to their ligands on leukocytes induces the activation of different signaling pathways (Figure 1B). Neutrophils rolling on P-selectin partially activate integrin αLβ2, also known as lymphocyte-associated antigen-1 (LFA-1), which slows their rolling velocities by enhancing transient LFA-1 binding to intercellular cell adhesion molecule-1 (ICAM-1). E- or P-selectin binding induces LFA-1 extension in a Syk-dependent manner.77  The cytoplasmic tail of PSGL-1 is required for LFA-1 activation and slower rolling on ICAM-1.78  However, deleting the cytoplasmic tail of PSGL-1 does not change the rolling of neutrophils on P-selectin or its localization in microvilli, lipid rafts, and uropods.78 

In transfected cells, PSGL-1 interacts with the p85 subunit of PI3K in the presence of Naf-1.33  Under nonflow conditions, stimulation of human neutrophils with a soluble P-selectin-Fc chimeric protein induces SFK-dependent phosphorylation of Naf-1, which recruits the phosphoinositide-3-OH kinase p85-p110δ (PI3Kδ) heterodimer and leads to leukocyte integrin activation.33  These conditions may occur as leukocytes adhere to activated platelets, which express P-selectin at high densities, but are less likely to occur as leukocytes roll on P-selectin expressed on activated endothelial cells. Indeed, murine neutrophils lacking PI3Kδ exhibit normal LFA-1-dependent slow rolling on P-selectin and ICAM-1.40 

Three studies using flow chambers have shown that PSGL-1 participates in E-selectin–mediated slow rolling of murine neutrophils.40,78,79  In one study using unfractionated murine blood, PSGL-1-deficient neutrophils did not roll slower on E-selectin and ICAM-1 than on E-selectin alone. In contrast, CD44-deficient neutrophils rolled much slower on E-selectin and ICAM-1 than on E-selectin alone, although they rolled slightly faster than wild-type neutrophils.79  In another study using isolated murine leukocytes, reduced rolling velocity was abolished only in neutrophils that lacked both PSGL-1 and CD44.40  In flow chamber experiments using whole human blood, blocking the N-terminal P-selectin–binding site on PSGL-1 with monovalent Fab fragments of mAb PL1 was sufficient to prevent slow rolling on E-selectin and ICAM-1, suggesting that PSGL-1 engagement is necessary for effective signaling in human neutrophils.77  This surprising result implies that the N-terminal region of PSGL-1 must engage E-selectin to trigger signaling because PSGL-1 has more than one binding site for E-selectin and PL1 does not completely block binding of PSGL-1 to E-selectin.80  Four in vivo studies failed to find a rolling velocity difference between murine wild-type and PSGL-1–deficient neutrophils.10,38-40  However, in these experiments, rolling behavior of knockout and wild-type cells could not be compared in the same microvessels. Natural variations in wall shear stress, vessel diameter, and flow velocity may introduce some experimental noise that can make small differences difficult to detect in vivo.79  On the other hand, intravenous injection of a blocking mAb to β2 integrins significantly increased rolling velocities in wild-type mice81  or in mice lacking PSGL-1 or CD44,40  suggesting that either PSGL-1 or CD44 is sufficient to trigger slow rolling in vivo. At present, technical differences probably account for these apparent discrepancies, and the relative roles of PSGL-1 and CD44 in E-selectin–triggered signaling require further study. To date, no direct physical interaction of PSGL-1 or CD44 with downstream signaling molecules has been demonstrated.

E-selectin ligand engagement on neutrophils induces signals that partially activate LFA-1, which mediates slow rolling on ICAM-1.77,79,82  E-selectin–mediated signaling requires intact lipid rafts on neutrophils40  and an intact cytoplasmic domain of PSGL-1.40  E-selectin binding induces the phosphorylation of the SFKs Fgr, Hck, and Lyn40,82  and of the ITAM-containing adaptor proteins DAP12 and FcRγ, which subsequently interact with the tyrosine kinase Syk.82  PSGL-140,77,79  or CD4440  and the activation of Syk79  are required for E-selectin–mediated slow rolling (Figure 1B). DAP12 and Syk phosphorylation is absent in neutrophils from Fgr−/− mice and Lyn−/−/Hck−/− mice after E-selectin engagement.40,82  Likewise, elimination of both ITAM-containing adaptor proteins, DAP12 and FcRγ, abolishes Syk phosphorylation and slow rolling.40,82  The Tec family kinase Bruton tyrosine kinase acts downstream of Syk40,83  and regulates 2 pathways: one requires phospholipase C-γ2; the other may require PI3K-γ,83  although another study did not observe this requirement.40  Because the rolling velocity defect in PI3Kγ-deficient neutrophils is small, it may fall below the limit of detection in some assays. The small GTPase Rap1 is activated after E-selectin engagement, and blocking Rap1a in Pik3cg−/− mice by a dominant-negative TAT-fusion mutant completely abolishes E-selectin–mediated slow rolling.84  CalDAG-GEFI (gene name Rasgrp2) and p38 MAPK are key signaling intermediates between phospholipase C-γ2 and Rap1a. Interestingly, the extension of LFA-1 induced by E-selectin binding is only partially dependent on CalDAG-GEFI, whereas chemokine-triggered LFA-1 activation is completely defective in Rasgrp2−/− mice.84 

ESL-1 also appears to contribute to the pro-adhesive action of E-selectin38,85  and probably cooperates with CD44 for this function as suggested by the observation that combined deficiency in both ligands results in elevated rolling flux fractions at the expense of reduced firm adhesion.38  These experiments also showed that slow leukocyte rolling requires ESL-1 to an extent similar to that described for CD44.38,39  Although there is evidence that signaling is defective when ESL-1 is not expressed,85  the precise function of ESL-1 in controlling slow rolling remains unknown. The rolling phenotype of ESL-1–deficient (as opposed to knocked-down, where silencing may be not fully specific) leukocytes has not been described. An interesting particularity of ESL-1 is its role in maintaining steady rolling kinetics by allowing continuous contact with the inflamed endothelium.38  Overall, these studies suggest that ESL-1 is a versatile ligand, capable of cooperating with PSGL-1 to mediate tethering on E-selectin while also contributing to steady rolling on endothelial cells once the leukocyte has tethered. Why ESL-1 is endowed with these functional properties is not well understood. One possibility is that its topologic distribution underlies this versatility: it is homogeneously expressed on the microvilli surface,69  whereas PSGL-1 expression is mostly restricted to the tips of these structures13  and CD44 is expressed in the planar cell body86  (Figure 1A).

Besides controlling rolling velocities, E-selectin ligand engagement also induces redistribution or “capping” of adhesion molecules on the cell surface of neutrophils.38,87  Interestingly, this effect appears to be exclusively mediated by CD44 and involves activation of p38 MAPK.38,87  Why receptor translation along the membrane is controlled by CD44 but not PSGL-1 is unknown. There is also evidence that engagement of PSGL-1 by P-selectin or E-selectin can trigger proliferative and differentiation signals in hematopoietic cells, including hematopoietic progenitors88  and dendritic cells,89  with functional consequences during inflammation.90  The signaling pathways controlling these processes have not been described.

Little is known about the possible pathophysiologic roles of ESL-1, but a potential contribution to vascular occlusion in sickle cell disease has been recently described.85  In a murine model of sickle cell disease after challenge with tumor necrosis factor-α, interactions between sickle-shaped erythrocytes and neutrophils generate intravascular cell aggregates that trigger the vaso-occlusive episodes characteristic of patients with this disease.85,91  In this murine model, ESL-1 transduces signals that activate integrin αMβ2 (also known as Mac-1) on neutrophils (Figure 1B), thus favoring interactions with circulating erythrocytes and promoting vaso-occlusion.85  PSGL-1 and CD44 do not contribute significantly to integrin activation in this model, which suggests ligand-specific signaling pathways. Indirect evidence with chemical inhibitors in vivo suggested that SFKs, but not p38 MAPK or Syk, are required for integrin activation downstream of ESL-1.85  Thus, although ESL-1 shares the SFK signaling pathway with PSGL-1 and CD44 to modulate integrin activation,33,40,82  it appears to have its own activating functions. One possible explanation is that each ligand has a temporally restricted signaling function: PSGL-1 and CD44 predominating during early (ie, tethering and rolling) phases of recruitment and ESL-1 at later stages (ie, during the crawling phase), but this hypothesis needs to be experimentally tested. How ESL-1 initiates signaling events on leukocytes also requires further study. Because ESL-1 is important for the processing and signaling of various growth factors,70,75  caution is needed to discriminate between effects that may be purely selectin-triggered and those related to other physiologic inputs.

E-selectin can bind to multiple glycoconjugates. Loss of PSGL-1, CD44, and ESL-1 in murine neutrophils virtually eliminates rolling on E-selectin, suggesting that these 3 glycoproteins compose all physiologically relevant ligands for E-selectin on these cells.38  However, loss of core 1-derived O-glycans in murine neutrophils also virtually eliminates rolling on E-selectin, even though CD44 and ESL-1 from these cells (which require N-glycans to bind to E-selectin) still bind to E-selectin in biochemical assays.26  One possible explanation for the discrepant results is that neutrophils express at least one more glycoprotein ligand for E-selectin that requires specific O-glycosylation. In the absence of this putative ligand, the N-glycans on CD44 and ESL-1 are insufficient to support rolling. In the absence of PSGL-1, CD44, and ESL-1, the O-glycans on this putative ligand are also insufficient to support rolling. Another possibility is that loss of core 1 O-glycans indirectly impairs the functions of CD44 and ESL-1 by altering their cell-surface distributions or by other mechanisms. A third possibility is that loss of the other biologic functions of ESL-1 affects neutrophil properties that indirectly impair rolling on E-selectin.

There is experimental evidence that a different combination of glycoproteins, including PSGL-1, CD44, and CD43, functions in murine inflammatory T cells.43,92-94  Furthermore, human neutrophils may use L-selectin and glycolipids to mediate E-selectin binding95,96  (Table 1). In vitro, E-selectin binds to human CD66/carcinoembryonic antigen,97  integrin Mac-1,98  podocalyxin-like protein, or melanoma cell adhesion molecule,99  which may be relevant in specific cellular contexts. Thus, the identification of the full repertoire of ligands for E-selectin is still a matter of debate and active research. We briefly summarize additional glycoconjugates on hematopoietic cells with stronger evidence as bona fide ligands for E-selectin.

Table 1

Comparison of mouse and human leukocyte ligands for endothelial selectins

Mouse
Human
FunctionEvidenceFunctionEvidence
PSGL-1 (PMN and T cells) Tethering to and rolling on P- and E- selectin Antibody blocking, and knockout mice, flow chamber and IVM Tethering to and rolling on P-selectin Antibody blocking, flow chamber 
 Signaling, β2 integrin activation for slow rolling on P- and E-selectin Flow chamber and IVM Signaling, integrin activation for slow rolling on E-selectin Antibody blocking, flow chamber 
CD44 (PMN and T cells) Cooperates with PSGL-1 for rolling on E-selectin IVM, flow chamber Contributes to binding to fluid-phase E-selectin Flow cytometry 
 Signaling for β2 integrin activation and slow rolling on E-selectin Knockout mice, flow chamber, IVM 
 Signaling for receptor clustering on E-selectin Knockout mice, IVM 
 Cooperates with PSGL-1 for leukocyte migration during inflammation Inflammatory models in knockout mice 
ESL-1 (PMN) Present on the surface of neutrophils and Th1 lymphocytes Surface biotinylation and Western blotting Not detected on the surface of human leukocytes Surface biotinylation and Western blotting 
 Binds to E-selectin E-selectin affinity columns Unknown contribution to E-selectin binding  
 Antibody blocking on myeloid cell line  
 Cooperates with PSGL-1 for tethering to E-selectin
Cooperates with CD44 for slow rolling on E-selectin
Allows steady rolling on E-selectin
Signaling for β2 integrin activation 
shRNA silencing and IVM  
CD43 (T cells) Cooperates with PSGL-1 for binding to E-selectin Flow cytometry and static adhesion in knockout mice Supports binding and rolling of E-selectin-expressing cells In vitro binding and blot-rolling assays 
 Cooperates with PSGL-1 for Th1 cell migration during inflammation Skin inflammation model in knockout mice  
L-selectin (PMN) Does not bind to P- or E-selectin E-selectin affinity columns and antibody blocking Binding to E-selectin E-selectin affinity columns 
 Binding to PSGL-1 mediates secondary tethers Flow chamber and IVM in knockout mice Mediates rolling on E-selectin Flow chamber and antibody blocking 
Glycolipids (PMN) Unknown contribution to selectin binding Ligands for P- and E-selectin are protease-sensitive Mediate rolling of E-selectin expressing cells Flow chamber and use of inhibitors of glycosphingolipid biosynthesis 
Other differences (PMN and T cells) Ligands for P- and E-selectin are protease sensitive Ligands for E-selectin are protease insensitive  
 Antibodies to sLex and Lex do not bind murine neutrophils Antibodies to sLex and Lex strongly bind to human neutrophils  
 PSGL-1, CD43, CD44 and ESL-1 cooperate for tethering, rolling and migration to inflamed sites Knockout and shRNA silencing using IVM, and inflammation models Unknown repertoire of E-selectin ligands; in vitro evidence exists for PSGL-1, CD44, L-selectin, and glycolipids on neutrophils; evidence for PSGL-1 and CD43 on T cells  
Mouse
Human
FunctionEvidenceFunctionEvidence
PSGL-1 (PMN and T cells) Tethering to and rolling on P- and E- selectin Antibody blocking, and knockout mice, flow chamber and IVM Tethering to and rolling on P-selectin Antibody blocking, flow chamber 
 Signaling, β2 integrin activation for slow rolling on P- and E-selectin Flow chamber and IVM Signaling, integrin activation for slow rolling on E-selectin Antibody blocking, flow chamber 
CD44 (PMN and T cells) Cooperates with PSGL-1 for rolling on E-selectin IVM, flow chamber Contributes to binding to fluid-phase E-selectin Flow cytometry 
 Signaling for β2 integrin activation and slow rolling on E-selectin Knockout mice, flow chamber, IVM 
 Signaling for receptor clustering on E-selectin Knockout mice, IVM 
 Cooperates with PSGL-1 for leukocyte migration during inflammation Inflammatory models in knockout mice 
ESL-1 (PMN) Present on the surface of neutrophils and Th1 lymphocytes Surface biotinylation and Western blotting Not detected on the surface of human leukocytes Surface biotinylation and Western blotting 
 Binds to E-selectin E-selectin affinity columns Unknown contribution to E-selectin binding  
 Antibody blocking on myeloid cell line  
 Cooperates with PSGL-1 for tethering to E-selectin
Cooperates with CD44 for slow rolling on E-selectin
Allows steady rolling on E-selectin
Signaling for β2 integrin activation 
shRNA silencing and IVM  
CD43 (T cells) Cooperates with PSGL-1 for binding to E-selectin Flow cytometry and static adhesion in knockout mice Supports binding and rolling of E-selectin-expressing cells In vitro binding and blot-rolling assays 
 Cooperates with PSGL-1 for Th1 cell migration during inflammation Skin inflammation model in knockout mice  
L-selectin (PMN) Does not bind to P- or E-selectin E-selectin affinity columns and antibody blocking Binding to E-selectin E-selectin affinity columns 
 Binding to PSGL-1 mediates secondary tethers Flow chamber and IVM in knockout mice Mediates rolling on E-selectin Flow chamber and antibody blocking 
Glycolipids (PMN) Unknown contribution to selectin binding Ligands for P- and E-selectin are protease-sensitive Mediate rolling of E-selectin expressing cells Flow chamber and use of inhibitors of glycosphingolipid biosynthesis 
Other differences (PMN and T cells) Ligands for P- and E-selectin are protease sensitive Ligands for E-selectin are protease insensitive  
 Antibodies to sLex and Lex do not bind murine neutrophils Antibodies to sLex and Lex strongly bind to human neutrophils  
 PSGL-1, CD43, CD44 and ESL-1 cooperate for tethering, rolling and migration to inflamed sites Knockout and shRNA silencing using IVM, and inflammation models Unknown repertoire of E-selectin ligands; in vitro evidence exists for PSGL-1, CD44, L-selectin, and glycolipids on neutrophils; evidence for PSGL-1 and CD43 on T cells  

Listed are glycoconjugates with strong evidence as P- or E-selectin ligands in at least some assays. The leukocyte subset (neutrophils, PMN; or T lymphocytes) for which the function of each putative ligand has been best studied is indicated in parentheses.

IVM indicates intravital microscopy; sLex, sialyl Lewis x structure; and Lex, Lewis x structure.

CD43

The high level of expression on leukocytes, extensive glycosylation, and molecular length of CD43 (also known as leukosialin) were proposed to favor both pro-adhesive or anti-adhesive roles.100,101  Biochemical and in vitro cellular studies as well as in vivo data support a role for CD43 as an E-selectin ligand on human and murine inflammatory T cells (Th1 type)93,102  but not on neutrophils.26,103  Delayed-type hypersensitivity models have been used to demonstrate the physiologic contribution of CD43 to skin inflammation during T cell–dependent responses. In all cases, ablation of PSGL-1 was required to unmask a role for CD43.92,94  Like PSGL-1, CD43 localizes to microvilli,13,104  but it is not known whether both receptors cooperate in mediating T-cell tethering. These findings, together with the observation that CD43 expression on murine neutrophils is not sufficient to support tethering, rolling, or recruitment in the absence of PSGL-1, CD44, and ESL-1,38  and the differential contributions of CD44 on murine T cells and neutrophils,43  are consistent with the proposal that lymphoid and myeloid cells use a different repertoire of selectin ligands.105 

L-selectin

This selectin is exclusively expressed on leukocytes, where it directs the migration of naive and central memory T cells to lymph nodes through recognition of glycoproteins expressed on high endothelial venules.106  L-selectin–deficient mice exhibit impaired leukocyte recruitment to sites of inflammation,107  which may reflect the inability of L-selectin–deficient neutrophils to bind to adherent neutrophils and neutrophil fragments.10  Furthermore, L-selectin is expressed on the tips of microvilli and, on human neutrophils, is decorated with N-glycans capped with sLex.95,108  L-selectin from human (but not mouse) neutrophils binds to E-selectin affinity columns and supports the rolling of E-selectin–transfected cells96  (Table 1). Antibodies that recognize the lectin domain of human L-selectin partially inhibit in vitro neutrophil rolling on E-selectin,95,96  but this was later explained by inhibition of secondary neutrophil-neutrophil tethering.109-111  In vivo, the reduced recruitment of leukocytes in L-selectin–deficient mice appears to be the result of loss of secondary tethers between circulating leukocytes and those already attached to the endothelium, which are mediated by interactions between L-selectin and PSGL-1.10 

Glycolipids

E-selectin binds to sialylated and fucosylated lactosylceramides extracted from human neutrophils,112  and immobilized lipids modified with sLex or sLea mediate tethering and rolling of E-selectin–expressing cells under flow.113  These early findings, performed mostly using human samples, conflict with the recent description that a limited array of glycoproteins accounts for the full repertoire of E-selectin ligand activity on mouse neutrophils.38  Given reported differences in the structure and function of selectin ligands between mouse and human neutrophils,6,96  it is conceivable that glycolipids play a more prominent role as E-selectin ligands in human neutrophils (Table 1). In agreement with this, sialylated glycosphingolipids containing several terminal repeats of N-acetyl-lactosamine with 2 or 3 fucose residues have been purified from human neutrophils. These glycosphingolipids support tethering and rolling of E-selectin–expressing cells at densities similar to those found on intact cells.114  Inhibition of glycosphingolipid synthesis on neutrophils partially abrogates E-selectin binding,114  although this finding could be explained by indirect effects through membrane stiffening.115  It has been proposed that the high density of glycolipids on the cell membrane compensates for their reduced accessibility compared with extended glycoproteins presented on microvilli.113  Thus, glycolipid-mediated interactions may be particularly important during the slow rolling phase, when the cell's body is in close proximity to the endothelial membrane. Notwithstanding these observations, the physiologic relevance of glycolipids for tethering and rolling of human neutrophils or other leukocyte subsets on E-selectin awaits definitive confirmation.

More than 2 decades after the initial description of selectins, the complete repertoire of physiologic ligands that interact with endothelial selectins remains to be elucidated. The precise nature of all ligands, their contribution to leukocyte rolling and signaling, and the possible interspecies differences (Table 1) remain to be identified. At the same time, because the majority of research on selectin ligands has focused on myeloid cell lines and neutrophils, it will be important to establish whether the same repertoire of ligands functions in other leukocyte subsets, including inflammatory T cells, hematopoietic progenitors, or leukemic cells. Differences in the use of ligands among these cell types could be exploited to interfere with the extravasation of damaging subsets (eg, self-reactive lymphocytes, pro-atherogenic monocytes, or leukemic clones) without compromising homeostatic host defense.

From a mechanistic standpoint, signaling initiated by engagement of various selectin ligands is now well established. However, the complete sequence of events leading from selectin engagement of PSGL-1 and CD44 at the cell surface to integrin activation needs to be fully characterized (Figure 1B). A number of signaling intermediaries have been identified, but the potential contributions of Ca2+, diacylglycerol, protein kinase C, or PI3Kγ remain to be defined. It will also be important to define the exact signaling mechanisms by which ESL-1 contributes to leukocyte recruitment. The continuous advances in this field are rapidly reshaping our perception of selectin ligands as specialized signal transducers in immune cells; this perception should open new therapeutic avenues for the treatment of vascular and immune disorders.

The authors thank Dr A. Urzainqui for helpful comments on the manuscript.

This work was supported by the Interdisciplinary Clinical Research Center (IZKF, Münster, Germany) and the German Research Foundation (A.Z.), the National Institutes of Health (K.L. and R.P.M.), a Ramón y Cajal fellowship, the Spanish Ministry of Science and Innovation, and the FP7-People-IRG Program (A.H.). The Centro Nacional de Investigaciones Cardiovasculares is supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation.

National Institutes of Health

Contribution: All authors wrote and edited the manuscript and designed the figures.

Conflict-of-interest disclosure: R.P.M. has interest in Selexys, a company that is developing inhibitors of selectins and selectin ligands. The remaining authors declare no competing financial interests.

Correspondence: Andrés Hidalgo, Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernandez Almagro 3, Madrid 28039, Spain; e-mail: ahidalgo@cnic.es.

1
Vestweber
 
D
Blanks
 
JE
Mechanisms that regulate the function of the selectins and their ligands.
Physiol Rev
1999
, vol. 
79
 
1
(pg. 
181
-
213
)
2
McEver
 
RP
Zhu
 
C
Rolling cell adhesion.
Annu Rev Cell Dev Biol
2010
, vol. 
26
 (pg. 
363
-
396
)
3
Ley
 
K
Laudanna
 
C
Cybulsky
 
MI
Nourshargh
 
S
Getting to the site of inflammation: the leukocyte adhesion cascade updated.
Nat Rev Immunol
2007
, vol. 
7
 
9
(pg. 
678
-
689
)
4
Homeister
 
JW
Thall
 
AD
Petryniak
 
B
, et al. 
The alpha(1,3)fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing.
Immunity
2001
, vol. 
15
 
1
(pg. 
115
-
126
)
5
Wilkins
 
PP
McEver
 
RP
Cummings
 
RD
Structures of the O-glycans on P-selectin glycoprotein ligand-1 from HL-60 cells.
J Biol Chem
1996
, vol. 
271
 
31
(pg. 
18732
-
18742
)
6
Kobzdej
 
MM
Leppanen
 
A
Ramachandran
 
V
Cummings
 
RD
McEver
 
RP
Discordant expression of selectin ligands and sialyl Lewis x-related epitopes on murine myeloid cells.
Blood
2002
, vol. 
100
 
13
(pg. 
4485
-
4494
)
7
Norman
 
KE
Moore
 
KL
McEver
 
RP
Ley
 
K
Leukocyte rolling in vivo is mediated by P-selectin glycoprotein ligand-1.
Blood
1995
, vol. 
86
 
12
(pg. 
4417
-
4421
)
8
Xia
 
L
Sperandio
 
M
Yago
 
T
, et al. 
P-selectin glycoprotein ligand-1-deficient mice have impaired leukocyte tethering to E-selectin under flow.
J Clin Invest
2002
, vol. 
109
 
7
(pg. 
939
-
950
)
9
Hirata
 
T
Merrill-Skoloff
 
G
Aab
 
M
Yang
 
J
Furie
 
BC
Furie
 
B
P-selectin glycoprotein ligand 1 (PSGL-1) is a physiological ligand for E-selectin in mediating T helper 1 lymphocyte migration.
J Exp Med
2000
, vol. 
192
 
11
(pg. 
1669
-
1676
)
10
Sperandio
 
M
Smith
 
ML
Forlow
 
SB
, et al. 
P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules.
J Exp Med
2003
, vol. 
197
 
10
(pg. 
1355
-
1363
)
11
Zarbock
 
A
Muller
 
H
Kuwano
 
Y
Ley
 
K
PSGL-1-dependent myeloid leukocyte activation.
J Leukoc Biol
2009
, vol. 
86
 
5
(pg. 
1119
-
1124
)
12
Del Conde
 
I
Shrimpton
 
CN
Thiagarajan
 
P
Lopez
 
JA
Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation.
Blood
2005
, vol. 
106
 
5
(pg. 
1604
-
1611
)
13
Moore
 
KL
Patel
 
KD
Bruehl
 
RE
, et al. 
P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin.
J Cell Biol
1995
, vol. 
128
 
4
(pg. 
661
-
671
)
14
McEver
 
RP
Ley
 
K
P-selectin glycoprotein ligand-1 (PSGL-1).
Adhesion Molecules: Function and Inhibition
2007
Basel, Switzerland
Birkhauser Verlag
(pg. 
3
-
26
)
15
McEver
 
RP
Cummings
 
RD
Role of PSGL-1 binding to selectins in leukocyte recruitment.
J Clin Invest
1997
, vol. 
100
 
11 suppl
(pg. 
S97
-
S103
)
16
Afshar-Kharghan
 
V
Diz-Kucukkaya
 
R
Ludwig
 
EH
Marian
 
AJ
Lopez
 
JA
Human polymorphism of P-selectin glycoprotein ligand 1 attributable to variable numbers of tandem decameric repeats in the mucinlike region.
Blood
2001
, vol. 
97
 
10
(pg. 
3306
-
3307
)
17
Yang
 
J
Galipeau
 
J
Kozak
 
CA
Furie
 
BC
Furie
 
B
Mouse P-selectin glycoprotein ligand-1: molecular cloning, chromosomal localization, and expression of a functional P-selectin receptor.
Blood
1996
, vol. 
87
 
10
(pg. 
4176
-
4186
)
18
Tenno
 
M
Ohtsubo
 
K
Hagen
 
FK
, et al. 
Initiation of protein O glycosylation by the polypeptide GalNAcT-1 in vascular biology and humoral immunity.
Mol Cell Biol
2007
, vol. 
27
 
24
(pg. 
8783
-
8796
)
19
Schachter
 
H
Brockhausen
 
I
The biosynthesis of branched O-glycans.
Symp Soc Exp Biol
1989
, vol. 
43
 (pg. 
1
-
26
)
20
Ellies
 
LG
Tsuboi
 
S
Petryniak
 
B
Lowe
 
JB
Fukuda
 
M
Marth
 
JD
Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation.
Immunity
1998
, vol. 
9
 
6
(pg. 
881
-
890
)
21
Smith
 
MJ
Smith
 
BR
Lawrence
 
MB
Snapp
 
KR
Functional analysis of the combined role of the O-linked branching enzyme core 2 beta1-6-N-glucosaminyltransferase and dimerization of P-selectin glycoprotein ligand-1 in rolling on P-selectin.
J Biol Chem
2004
, vol. 
279
 
21
(pg. 
21984
-
21991
)
22
Snapp
 
KR
Heitzig
 
CE
Ellies
 
LG
Marth
 
JD
Kansas
 
GS
Differential requirements for the O-linked branching enzyme core 2 beta1-6-N-glucosaminyltransferase in biosynthesis of ligands for E-selectin and P-selectin.
Blood
2001
, vol. 
97
 
12
(pg. 
3806
-
3811
)
23
Sperandio
 
M
Thatte
 
A
Foy
 
D
Ellies
 
LG
Marth
 
JD
Ley
 
K
Severe impairment of leukocyte rolling in venules of core 2 glucosaminyltransferase-deficient mice.
Blood
2001
, vol. 
97
 
12
(pg. 
3812
-
3819
)
24
Xia
 
L
Ramachandran
 
V
McDaniel
 
JM
Nguyen
 
KN
Cummings
 
RD
McEver
 
RP
N-terminal residues in murine P-selectin glycoprotein ligand-1 required for binding to murine P-selectin.
Blood
2003
, vol. 
101
 
2
(pg. 
552
-
559
)
25
Westmuckett
 
AD
Thacker
 
KM
Moore
 
KL
Tyrosine sulfation of native mouse Psgl-1 is required for optimal leukocyte rolling on p-selectin in vivo.
PLoS One
2011
, vol. 
6
 
5
pg. 
e20406
 
26
Yago
 
T
Fu
 
J
McDaniel
 
JM
Miner
 
JJ
McEver
 
RP
Xia
 
L
Core 1-derived O-glycans are essential E-selectin ligands on neutrophils.
Proc Natl Acad Sci U S A
2010
, vol. 
107
 
20
(pg. 
9204
-
9209
)
27
Hirata
 
T
Furukawa
 
Y
Yang
 
BG
, et al. 
Human P-selectin glycoprotein ligand-1 (PSGL-1) interacts with the skin-associated chemokine CCL27 via sulfated tyrosines at the PSGL-1 amino terminus.
J Biol Chem
2004
, vol. 
279
 
50
(pg. 
51775
-
51782
)
28
Veerman
 
KM
Williams
 
MJ
Uchimura
 
K
, et al. 
Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs.
Nat Immunol
2007
, vol. 
8
 
5
(pg. 
532
-
539
)
29
Epperson
 
TK
Patel
 
KD
McEver
 
RP
Cummings
 
RD
Noncovalent association of P-selectin glycoprotein ligand-1 and minimal determinants for binding to P-selectin.
J Biol Chem
2000
, vol. 
275
 
11
(pg. 
7839
-
7853
)
30
Miner
 
JJ
Shao
 
B
Wang
 
Y
, et al. 
Cytoplasmic domain of P-selectin glycoprotein ligand-1 facilitates dimerization and export from the endoplasmic reticulum.
J Biol Chem
2011
, vol. 
286
 
11
(pg. 
9577
-
9586
)
31
Alonso-Lebrero
 
JL
Serrador
 
JM
Dominguez-Jimenez
 
C
, et al. 
Polarization and interaction of adhesion molecules P-selectin glycoprotein ligand 1 and intercellular adhesion molecule 3 with moesin and ezrin in myeloid cells.
Blood
2000
, vol. 
95
 
7
(pg. 
2413
-
2419
)
32
Urzainqui
 
A
Serrador
 
JM
Viedma
 
F
, et al. 
ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1.
Immunity
2002
, vol. 
17
 
4
(pg. 
401
-
412
)
33
Wang
 
HB
Wang
 
JT
Zhang
 
L
, et al. 
P-selectin primes leukocyte integrin activation during inflammation.
Nat Immunol
2007
, vol. 
8
 
8
(pg. 
882
-
892
)
34
Schaff
 
UY
Shih
 
HH
Lorenz
 
M
, et al. 
SLIC-1/sorting nexin 20: a novel sorting nexin that directs subcellular distribution of PSGL-1.
Eur J Immunol
2008
, vol. 
38
 
2
(pg. 
550
-
564
)
35
Borges
 
E
Eytner
 
R
Moll
 
T
, et al. 
The P-selectin glycoprotein ligand-1 is important for recruitment of neutrophils into inflamed mouse peritoneum.
Blood
1997
, vol. 
90
 
5
(pg. 
1934
-
1942
)
36
Borges
 
E
Tietz
 
W
Steegmaier
 
M
, et al. 
P-selectin glycoprotein ligand-1 (PSGL-1) on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin.
J Exp Med
1997
, vol. 
185
 
3
(pg. 
573
-
578
)
37
Yang
 
J
Hirata
 
T
Croce
 
K
, et al. 
Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil rolling and migration.
J Exp Med
1999
, vol. 
190
 
12
(pg. 
1769
-
1782
)
38
Hidalgo
 
A
Peired
 
AJ
Wild
 
MK
Vestweber
 
D
Frenette
 
PS
Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44.
Immunity
2007
, vol. 
26
 
4
(pg. 
477
-
489
)
39
Katayama
 
Y
Hidalgo
 
A
Chang
 
J
Peired
 
A
Frenette
 
PS
CD44 is a physiological E-selectin ligand on neutrophils.
J Exp Med
2005
, vol. 
201
 
8
(pg. 
1183
-
1189
)
40
Yago
 
T
Shao
 
B
Miner
 
JJ
, et al. 
E-selectin engages PSGL-1 and CD44 through a common signaling pathway to induce integrin alphaLbeta2-mediated slow leukocyte rolling.
Blood
2010
, vol. 
116
 
3
(pg. 
485
-
494
)
41
Merzaban
 
JS
Burdick
 
MM
Gadhoum
 
SZ
, et al. 
Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells.
Blood
2011
, vol. 
118
 
7
(pg. 
1774
-
1783
)
42
Sackstein
 
R
The bone marrow is akin to skin: HCELL and the biology of hematopoietic stem cell homing.
J Invest Dermatol
2004
, vol. 
122
 
5
(pg. 
1061
-
1069
)
43
Nacher
 
M
Blazquez
 
AB
Shao
 
B
, et al. 
Physiological contribution of CD44 as a ligand for E-selectin during inflammatory T-cell recruitment.
Am J Pathol
2011
, vol. 
178
 
5
(pg. 
2437
-
2446
)
44
Screaton
 
GR
Bell
 
MV
Jackson
 
DG
Cornelis
 
FB
Gerth
 
U
Bell
 
JI
Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons.
Proc Natl Acad Sci U S A
1992
, vol. 
89
 
24
(pg. 
12160
-
12164
)
45
Lesley
 
J
Hyman
 
R
Kincade
 
PW
CD44 and its interaction with extracellular matrix.
Adv Immunol
1993
, vol. 
54
 (pg. 
271
-
335
)
46
Ruiz
 
P
Schwarzler
 
C
Gunthert
 
U
CD44 isoforms during differentiation and development.
Bioessays
1995
, vol. 
17
 
1
(pg. 
17
-
24
)
47
Sherman
 
L
Sleeman
 
J
Herrlich
 
P
Ponta
 
H
Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression.
Curr Opin Cell Biol
1994
, vol. 
6
 
5
(pg. 
726
-
733
)
48
Sleeman
 
JP
Kondo
 
K
Moll
 
J
Ponta
 
H
Herrlich
 
P
Variant exons v6 and v7 together expand the repertoire of glycosaminoglycans bound by CD44.
J Biol Chem
1997
, vol. 
272
 
50
(pg. 
31837
-
31844
)
49
Katoh
 
S
Miyagi
 
T
Taniguchi
 
H
, et al. 
Cutting edge: an inducible sialidase regulates the hyaluronic acid binding ability of CD44-bearing human monocytes.
J Immunol
1999
, vol. 
162
 
9
(pg. 
5058
-
5061
)
50
Maiti
 
A
Maki
 
G
Johnson
 
P
TNF-alpha induction of CD44-mediated leukocyte adhesion by sulfation.
Science
1998
, vol. 
282
 
5390
(pg. 
941
-
943
)
51
Skelton
 
TP
Zeng
 
C
Nocks
 
A
Stamenkovic
 
I
Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan.
J Cell Biol
1998
, vol. 
140
 
2
(pg. 
431
-
446
)
52
Levesque
 
MC
Haynes
 
BF
Cytokine induction of the ability of human monocyte CD44 to bind hyaluronan is mediated primarily by TNF-alpha and is inhibited by IL-4 and IL-13.
J Immunol
1997
, vol. 
159
 
12
(pg. 
6184
-
6194
)
53
Perschl
 
A
Lesley
 
J
English
 
N
Hyman
 
R
Trowbridge
 
IS
Transmembrane domain of CD44 is required for its detergent insolubility in fibroblasts.
J Cell Sci
1995
, vol. 
108
 
3
(pg. 
1033
-
1041
)
54
Ponta
 
H
Sherman
 
L
Herrlich
 
PA
CD44: from adhesion molecules to signalling regulators.
Nat Rev Mol Cell Biol
2003
, vol. 
4
 
1
(pg. 
33
-
45
)
55
Schmits
 
R
Filmus
 
J
Gerwin
 
N
, et al. 
CD44 regulates hematopoietic progenitor distribution, granuloma formation, and tumorigenicity.
Blood
1997
, vol. 
90
 
6
(pg. 
2217
-
2233
)
56
Bonder
 
CS
Clark
 
SR
Norman
 
MU
Johnson
 
P
Kubes
 
P
Use of CD44 by CD4+ Th1 and Th2 lymphocytes to roll and adhere.
Blood
2006
, vol. 
107
 
12
(pg. 
4798
-
4806
)
57
DeGrendele
 
HC
Estess
 
P
Picker
 
LF
Siegelman
 
MH
CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway.
J Exp Med
1996
, vol. 
183
 
3
(pg. 
1119
-
1130
)
58
DeGrendele
 
HC
Estess
 
P
Siegelman
 
MH
Requirement for CD44 in activated T cell extravasation into an inflammatory site.
Science
1997
, vol. 
278
 
5338
(pg. 
672
-
675
)
59
DeGrendele
 
HC
Kosfiszer
 
M
Estess
 
P
Siegelman
 
MH
CD44 activation and associated primary adhesion is inducible via T cell receptor stimulation.
J Immunol
1997
, vol. 
159
 
6
(pg. 
2549
-
2553
)
60
Hutas
 
G
Bajnok
 
E
Gal
 
I
Finnegan
 
A
Glant
 
TT
Mikecz
 
K
CD44-specific antibody treatment and CD44 deficiency exert distinct effects on leukocyte recruitment in experimental arthritis.
Blood
2008
, vol. 
112
 
13
(pg. 
4999
-
5006
)
61
Khan
 
AI
Kerfoot
 
SM
Heit
 
B
, et al. 
Role of CD44 and hyaluronan in neutrophil recruitment.
J Immunol
2004
, vol. 
173
 
12
(pg. 
7594
-
7601
)
62
McDonald
 
B
McAvoy
 
EF
Lam
 
F
, et al. 
Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids.
J Exp Med
2008
, vol. 
205
 
4
(pg. 
915
-
927
)
63
Szanto
 
S
Gal
 
I
Gonda
 
A
Glant
 
TT
Mikecz
 
K
Expression of L-selectin, but not CD44, is required for early neutrophil extravasation in antigen-induced arthritis.
J Immunol
2004
, vol. 
172
 
11
(pg. 
6723
-
6734
)
64
Siegelman
 
MH
Stanescu
 
D
Estess
 
P
The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion.
J Clin Invest
2000
, vol. 
105
 
5
(pg. 
683
-
691
)
65
Nandi
 
A
Estess
 
P
Siegelman
 
M
Bimolecular complex between rolling and firm adhesion receptors required for cell arrest: CD44 association with VLA-4 in T cell extravasation.
Immunity
2004
, vol. 
20
 
4
(pg. 
455
-
465
)
66
Gonatas
 
JO
Mourelatos
 
A
Stieber
 
A
Lane
 
WS
Brosius
 
J
Gonatas
 
NK
MG-160, a membrane sialoglycoprotein of the medial cisternae of the rat Golgi apparatus, binds basic fibroblast growth factor and exhibits a high level of sequence identity to a chicken fibroblast growth factor receptor.
J Cell Sci
1995
, vol. 
108
 
2
(pg. 
457
-
467
)
67
Steegmaier
 
M
Levinovitz
 
A
Isenmann
 
S
, et al. 
The E-selectin-ligand ESL-1 is a variant of a receptor for fibroblast growth factor.
Nature
1995
, vol. 
373
 
6515
(pg. 
615
-
620
)
68
Gonatas
 
JO
Chen
 
YJ
Stieber
 
A
Mourelatos
 
Z
Gonatas
 
NK
Truncations of the C-terminal cytoplasmic domain of MG160, a medial Golgi sialoglycoprotein, result in its partial transport to the plasma membrane and filopodia.
J Cell Sci
1998
, vol. 
111
 
2
(pg. 
249
-
260
)
69
Steegmaier
 
M
Borges
 
E
Berger
 
J
Schwarz
 
H
Vestweber
 
D
The E-selectin-ligand ESL-1 is located in the Golgi as well as on microvilli on the cell surface.
J Cell Sci
1997
, vol. 
110
 
6
(pg. 
687
-
694
)
70
Miyaoka
 
Y
Tanaka
 
M
Imamura
 
T
Takada
 
S
Miyajima
 
A
A novel regulatory mechanism for Fgf18 signaling involving cysteine-rich FGF receptor (Cfr) and delta-like protein (Dlk).
Development
2010
, vol. 
137
 
1
(pg. 
159
-
167
)
71
Dimitroff
 
CJ
Descheny
 
L
Trujillo
 
N
, et al. 
Identification of leukocyte E-selectin ligands, P-selectin glycoprotein ligand-1 and E-selectin ligand-1, on human metastatic prostate tumor cells.
Cancer Res
2005
, vol. 
65
 
13
(pg. 
5750
-
5760
)
72
Lenter
 
M
Levinovitz
 
A
Isenmann
 
S
Vestweber
 
D
Monospecific and common glycoprotein ligands for E- and P-selectin on myeloid cells.
J Cell Biol
1994
, vol. 
125
 
2
(pg. 
471
-
481
)
73
Levinovitz
 
A
Muhlhoff
 
J
Isenmann
 
S
Vestweber
 
D
Identification of a glycoprotein ligand for E-selectin on mouse myeloid cells.
J Cell Biol
1993
, vol. 
121
 
2
(pg. 
449
-
459
)
74
Zhou
 
Z
Zuber
 
ME
Burrus
 
LW
Olwin
 
BB
Identification and characterization of a fibroblast growth factor (FGF) binding domain in the cysteine-rich FGF receptor.
J Biol Chem
1997
, vol. 
272
 
8
(pg. 
5167
-
5174
)
75
Yang
 
T
Mendoza-Londono
 
R
Lu
 
H
, et al. 
E-selectin ligand-1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-beta.
J Clin Invest
2010
, vol. 
120
 
7
(pg. 
2474
-
2485
)
76
Huang
 
MC
Zollner
 
O
Moll
 
T
, et al. 
P-selectin glycoprotein ligand-1 and E-selectin ligand-1 are differentially modified by fucosyltransferases Fuc-TIV and Fuc-TVII in mouse neutrophils.
J Biol Chem
2000
, vol. 
275
 
40
(pg. 
31353
-
31360
)
77
Kuwano
 
Y
Spelten
 
O
Zhang
 
H
Ley
 
K
Zarbock
 
A
Rolling on E- or P-selectin induces the extended but not high-affinity conformation of LFA-1 in neutrophils.
Blood
2010
, vol. 
116
 
4
(pg. 
617
-
624
)
78
Miner
 
JJ
Xia
 
L
Yago
 
T
, et al. 
Separable requirements for cytoplasmic domain of PSGL-1 in leukocyte rolling and signaling under flow.
Blood
2008
, vol. 
112
 
5
(pg. 
2035
-
2045
)
79
Zarbock
 
A
Lowell
 
CA
Ley
 
K
Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1.
Immunity
2007
, vol. 
26
 
6
(pg. 
773
-
783
)
80
Patel
 
KD
Moore
 
KL
Nollert
 
MU
McEver
 
RP
Neutrophils use both shared and distinct mechanisms to adhere to selectins under static and flow conditions.
J Clin Invest
1995
, vol. 
96
 
4
(pg. 
1887
-
1896
)
81
Dunne
 
JL
Ballantyne
 
CM
Beaudet
 
AL
Ley
 
K
Control of leukocyte rolling velocity in TNF-alpha-induced inflammation by LFA-1 and Mac-1.
Blood
2002
, vol. 
99
 
1
(pg. 
336
-
341
)
82
Zarbock
 
A
Abram
 
CL
Hundt
 
M
Altman
 
A
Lowell
 
CA
Ley
 
K
PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling.
J Exp Med
2008
, vol. 
205
 
10
(pg. 
2339
-
2347
)
83
Mueller
 
H
Stadtmann
 
A
Van Aken
 
H
, et al. 
Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways.
Blood
2010
, vol. 
115
 
15
(pg. 
3118
-
3127
)
84
Stadtmann
 
A
Brinkhaus
 
L
Mueller
 
H
, et al. 
Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling.
Eur J Immunol
2011
, vol. 
41
 
7
(pg. 
2074
-
2085
)
85
Hidalgo
 
A
Chang
 
J
Jang
 
JE
Peired
 
AJ
Chiang
 
EY
Frenette
 
PS
Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury.
Nat Med
2009
, vol. 
15
 
4
(pg. 
384
-
391
)
86
von Andrian
 
UH
Hasslen
 
SR
Nelson
 
RD
Erlandsen
 
SL
Butcher
 
EC
A central role for microvillous receptor presentation in leukocyte adhesion under flow.
Cell
1995
, vol. 
82
 
6
(pg. 
989
-
999
)
87
Green
 
CE
Pearson
 
DN
Camphausen
 
RT
Staunton
 
DE
Simon
 
SI
Shear-dependent capping of L-selectin and P-selectin glycoprotein ligand 1 by E-selectin signals activation of high-avidity beta2-integrin on neutrophils.
J Immunol
2004
, vol. 
172
 
12
(pg. 
7780
-
7790
)
88
Eto
 
T
Winkler
 
I
Purton
 
LE
Levesque
 
JP
Contrasting effects of P-selectin and E-selectin on the differentiation of murine hematopoietic progenitor cells.
Exp Hematol
2005
, vol. 
33
 
2
(pg. 
232
-
242
)
89
Urzainqui
 
A
Martinez
 
G
del Hoyo
 
A
, et al. 
Functional role of P-selectin glycoprotein ligand 1/P-selectin interaction in the generation of tolerogenic dendritic cells.
J Immunol
2007
, vol. 
179
 
11
(pg. 
7457
-
7465
)
90
Nunez-Andrade
 
N
Lamana
 
A
Sancho
 
D
, et al. 
P-selectin glycoprotein ligand-1 modulates immune inflammatory responses in the enteric lamina propria.
J Pathol
2011
, vol. 
224
 
2
(pg. 
212
-
221
)
91
Turhan
 
A
Weiss
 
LA
Mohandas
 
N
Coller
 
BS
Frenette
 
PS
Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm.
Proc Natl Acad Sci U S A
2002
, vol. 
99
 
5
(pg. 
3047
-
3051
)
92
Alcaide
 
P
King
 
SL
Dimitroff
 
CJ
Lim
 
YC
Fuhlbrigge
 
RC
Luscinskas
 
FW
The 130-kDa glycoform of CD43 functions as an E-selectin ligand for activated Th1 cells in vitro and in delayed-type hypersensitivity reactions in vivo.
J Invest Dermatol
2007
, vol. 
127
 
8
(pg. 
1964
-
1972
)
93
Matsumoto
 
M
Atarashi
 
K
Umemoto
 
E
, et al. 
CD43 functions as a ligand for E-selectin on activated T cells.
J Immunol
2005
, vol. 
175
 
12
(pg. 
8042
-
8050
)
94
Matsumoto
 
M
Shigeta
 
A
Furukawa
 
Y
Tanaka
 
T
Miyasaka
 
M
Hirata
 
T
CD43 collaborates with P-selectin glycoprotein ligand-1 to mediate E-selectin-dependent T cell migration into inflamed skin.
J Immunol
2007
, vol. 
178
 
4
(pg. 
2499
-
2506
)
95
Picker
 
LJ
Warnock
 
RA
Burns
 
AR
Doerschuk
 
CM
Berg
 
EL
Butcher
 
EC
The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140.
Cell
1991
, vol. 
66
 
5
(pg. 
921
-
933
)
96
Zollner
 
O
Lenter
 
MC
Blanks
 
JE
, et al. 
L-selectin from human, but not from mouse neutrophils binds directly to E-selectin.
J Cell Biol
1997
, vol. 
136
 
3
(pg. 
707
-
716
)
97
Kuijpers
 
TW
Hoogerwerf
 
M
van der Laan
 
LJ
, et al. 
CD66 nonspecific cross-reacting antigens are involved in neutrophil adherence to cytokine-activated endothelial cells.
J Cell Biol
1992
, vol. 
118
 
2
(pg. 
457
-
466
)
98
Crutchfield
 
KL
Shinde
 
VR
Patil
 
CJ
, et al. 
CD11b/CD18-coated microspheres attach to E-selectin under flow.
J Leukoc Biol
2000
, vol. 
67
 
2
(pg. 
196
-
205
)
99
Barthel
 
SR
Wiese
 
GK
Cho
 
J
, et al. 
Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking.
Proc Natl Acad Sci U S A
2009
, vol. 
106
 
46
(pg. 
19491
-
19496
)
100
Stockton
 
BM
Cheng
 
G
Manjunath
 
N
Ardman
 
B
von Andrian
 
UH
Negative regulation of T cell homing by CD43.
Immunity
1998
, vol. 
8
 
3
(pg. 
373
-
381
)
101
Woodman
 
RC
Johnston
 
B
Hickey
 
MJ
, et al. 
The functional paradox of CD43 in leukocyte recruitment: a study using CD43-deficient mice.
J Exp Med
1998
, vol. 
188
 
11
(pg. 
2181
-
2186
)
102
Fuhlbrigge
 
RC
King
 
SL
Sackstein
 
R
Kupper
 
TS
CD43 is a ligand for E-selectin on CLA+ human T cells.
Blood
2006
, vol. 
107
 
4
(pg. 
1421
-
1426
)
103
Carlow
 
DA
Ziltener
 
HJ
CD43 deficiency has no impact in competitive in vivo assays of neutrophil or activated T cell recruitment efficiency.
J Immunol
2006
, vol. 
177
 
9
(pg. 
6450
-
6459
)
104
Yonemura
 
S
Nagafuchi
 
A
Sato
 
N
Tsukita
 
S
Concentration of an integral membrane protein, CD43 (leukosialin, sialophorin), in the cleavage furrow through the interaction of its cytoplasmic domain with actin-based cytoskeletons.
J Cell Biol
1993
, vol. 
120
 
2
(pg. 
437
-
449
)
105
Varki
 
A
Selectin ligands.
Proc Natl Acad Sci U S A
1994
, vol. 
91
 
16
(pg. 
7390
-
7397
)
106
von Andrian
 
UH
Mempel
 
TR
Homing and cellular traffic in lymph nodes.
Nat Rev Immunol
2003
, vol. 
3
 
11
(pg. 
867
-
878
)
107
Tedder
 
TF
Steeber
 
DA
Pizcueta
 
P
L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.
J Exp Med
1995
, vol. 
181
 
6
(pg. 
2259
-
2264
)
108
Stein
 
JV
Cheng
 
G
Stockton
 
BM
Fors
 
BP
Butcher
 
EC
von Andrian
 
UH
L-selectin-mediated leukocyte adhesion in vivo: microvillous distribution determines tethering efficiency, but not rolling velocity.
J Exp Med
1999
, vol. 
189
 
1
(pg. 
37
-
50
)
109
Alon
 
R
Fuhlbrigge
 
RC
Finger
 
EB
Springer
 
TA
Interactions through L-selectin between leukocytes and adherent leukocytes nucleate rolling adhesions on selectins and VCAM-1 in shear flow.
J Cell Biol
1996
, vol. 
135
 
3
(pg. 
849
-
865
)
110
Guyer
 
DA
Moore
 
KL
Lynam
 
EB
, et al. 
P-selectin glycoprotein ligand-1 (PSGL-1) is a ligand for L-selectin in neutrophil aggregation.
Blood
1996
, vol. 
88
 
7
(pg. 
2415
-
2421
)
111
Walcheck
 
B
Moore
 
KL
McEver
 
RP
Kishimoto
 
TK
Neutrophil-neutrophil interactions under hydrodynamic shear stress involve L-selectin and PSGL-1: a mechanism that amplifies initial leukocyte accumulation of P-selectin in vitro.
J Clin Invest
1996
, vol. 
98
 
5
(pg. 
1081
-
1087
)
112
Tiemeyer
 
M
Swiedler
 
SJ
Ishihara
 
M
, et al. 
Carbohydrate ligands for endothelial-leukocyte adhesion molecule 1.
Proc Natl Acad Sci U S A
1991
, vol. 
88
 
4
(pg. 
1138
-
1142
)
113
Alon
 
R
Feizi
 
T
Yuen
 
CT
Fuhlbrigge
 
RC
Springer
 
TA
Glycolipid ligands for selectins support leukocyte tethering and rolling under physiologic flow conditions.
J Immunol
1995
, vol. 
154
 
10
(pg. 
5356
-
5366
)
114
Nimrichter
 
L
Burdick
 
MM
Aoki
 
K
, et al. 
E-selectin receptors on human leukocytes.
Blood
2008
, vol. 
112
 
9
(pg. 
3744
-
3752
)
115
Yago
 
T
Leppanen
 
A
Qiu
 
H
, et al. 
Distinct molecular and cellular contributions to stabilizing selectin-mediated rolling under flow.
J Cell Biol
2002
, vol. 
158
 
4
(pg. 
787
-
799
)
Sign in via your Institution