A new siglec family member, siglec‐10, is expressed in cells of the immune system and has signaling properties similar to CD33

Whitney, Gena S.; Wang, Shulin; Han, Chang; Cheng, Ke-Yi; Lu, Pin Hsuan; Zhou, Xia; Yang, Wen-Pin; McKinnon, Murray; Longphre, Malinda

doi:10.1046/j.0014-2956.2001.02543.x

Cited by 88 publications

(52 citation statements)

References 39 publications

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“…*P Ͻ .0005; **P Յ .005; ***P Ͻ .05. member of the Siglec family expressed on eosinophils, albeit at much lower levels than on monocytes and natural killer (NK) cells. 9,23 Thus, it appears that Siglec-8 is most specific for eosinophils. Initial studies of Siglec-8 suggested that the molecule had an uncharacteristically short cytoplasmic tail with no known signaling motifs.…”

Section: Discussionmentioning

confidence: 99%

Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis

Nutku

Aizawa

Hudson

et al. 2003

Blood

287

265

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IntroductionEosinophils, through release of preformed and newly generated mediators, are considered key effector cells in several diseases. Their recruitment and activation are regarded as central to the pathophysiology of allergic disorders, including asthma. [1][2][3] Besides selective migration, increased cell survival and decreased apoptosis have been proposed as mechanisms contributing to tissue-specific accumulation of these inflammatory cells. 4 Hence, therapeutic efforts in the area of allergic inflammation continue to focus on the development of agents to suppress eosinophil recruitment, activation, and survival.As a result of molecular efforts to identify novel, specific markers expressed on eosinophils, our group and others recently discovered Siglec-8, formerly called SAF-2. 5,6 Sialic acid binding immunoglobulin-like lectins (Siglecs) belong to the immunoglobulin (Ig) supergene family and characteristically have an N-terminal V-set domain that binds sialic acid. 7 Although originally isolated from a human eosinophil cDNA library by random expressed sequence tag sequencing, Siglec-8 is also expressed on human basophils and mast cells 5 and exists in 2 isoforms with identical extracellular and transmembrane sequences. One isoform (Siglec-8) has a short cytoplasmic tail with no known signaling sequences, while the other, Siglec-8 long form (Siglec-8L), has a longer cytoplasmic tail containing 2 tyrosine-based signaling motifs. 8,9 Although the function of Siglec-8 and Siglec-8L, and indeed most Siglecs, is unknown, the cytoplasmic region of Siglec-8L contains one consensus immunoreceptor tyrosine-based inhibitory motif (ITIM) and a signaling lymphocyte activation molecule (SLAM)-like motif, suggesting that Siglec-8L may possess signal transduction activity. 7-9 Indeed, for some Siglecs, such as Siglec-3 and Siglec-7 (p75/AIRM-1), antibody crosslinking has been shown to inhibit proliferation and survival of myeloid leukemic cells. 10-12 Therefore we hypothesized that ligation of Siglec-8 would inhibit eosinophil survival, and we present data that show a proapoptotic effect with antibody-mediated cross-linking. Materials and methods Antibodies and recombinant proteinsMurine monoclonal IgG 1 isotype antibodies (Abs) recognizing Siglec-8 (2E2, 2C4, and 9G4) were generated using previously described methods 5 and were endotoxin-free (ie, below the detection level of Ͻ 0.01 EU/mL as determined by amebocyte lysate assay; BioWhittaker, Walkersville, MD). Unless noted otherwise, these monoclonal Abs (mAbs) were used at saturating concentrations (2.5 g/mL). Normal sheep serum and goat antisheep horseradish peroxidase-linked Abs were from Calbiochem (La Jolla, CA). Goat antirabbit horseradish peroxidase-linked Ab was from Amersham Pharmacia Biotech (Piscataway, NJ). Polyclonal intact and F(abЈ) 2 goat antimouse IgG (heavy and light chain) were purchased from Caltag Laboratories (Burlingame, CA). Recombinant human interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were from R&D Syst...

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Section: Discussionmentioning

confidence: 99%

Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis

Nutku

Aizawa

Hudson

et al. 2003

Blood

287

265

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“…31,32 Taking into account the expression pattern and binding properties of Siglec-10, it has the characteristics to be a ligand for endothelial VAP-1. Although the sequence match between the enriched peptide and Siglec-10 is not perfect, the sequence contained several amino acids with similar properties.…”

Section: Discussionmentioning

confidence: 99%

Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate

Kivi

Elima

Aalto

et al. 2009

Blood

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Leukocytes migrate from the blood into areas of inflammation by interacting with various adhesion molecules on endothelial cells. Vascular adhesion protein-1 (VAP-1) is a glycoprotein expressed on inflamed endothelium where it plays a dual role: it is both an enzyme that oxidizes primary amines and an adhesin that is involved in leukocyte trafficking to sites of inflammation. Although VAP-1 was identified more than 15 years ago, the counterreceptor(s) for VAP-1 on leukocytes has remained unknown. Here we have identified Siglec-10 as a leukocyte ligand for VAP-1 using phage display screenings. The binding between Siglec-10 and VAP-1 was verified by different adhesion assays, and this interaction was also consistent with molecular modeling. Moreover, the interaction between Siglec-10 and VAP-1 led to increased hydrogen peroxide production, indicating that Siglec-10 serves as a substrate for VAP-1. Thus, the Siglec-10-VAP-1 interaction seems to mediate lymphocyte adhesion to endothelium and has the potential to modify the inflammatory microenvironment via the enzymatic end products. IntroductionMaintenance of an adequate immune defense is largely dependent on migration of circulating leukocytes from the vasculature into the surrounding tissue. Extravasation of leukocytes from the blood into the tissues is controlled by a multistep cascade, which involves numerous adhesion and signaling molecules. First, leukocytes tether and roll on the vascular endothelium, after which they adhere more strongly, arrest, and finally diapedese through the vessel wall. 1,2 One of the endothelial molecules involved in this cascade is a 180-kDa homodimeric glycoprotein, vascular adhesion protein-1 (VAP-1). 3 VAP-1 is mainly expressed on vascular endothelium, on smooth muscle cells, and on adipocytes. 4 It is rapidly translocated to the endothelial cell surface on inflammation, where it supports recruitment of leukocytes. 5,6 VAP-1 is involved in the rolling, firm adhesion, and transmigration phases of the extravasation cascade. Besides being an adhesin, VAP-1 is also an enzyme (semicarbazide sensitive amine oxidase, SSAO) and catalyzes oxidative deamination of a primary amine to an aldehyde with concomitant release of hydrogen peroxide and ammonium. 4 We and others have shown that VAP-1 supports leukocyte recruitment to sites of inflammation via both enzyme-activity-dependent and enzyme-activity-independent ways. Monoclonal anti-VAP-1 antibodies, which do not block the enzymatic activity of VAP-1, still block the binding of leukocytes to the endothelium in vitro and in vivo, and inhibitors of the enzymatic function of VAP-1 are able to effectively prevent the interaction between leukocytes and endothelium in vitro and in vivo. 7,8 Moreover, it has been recently shown that the end products generated by the catalytic activity of VAP-1, especially hydrogen peroxide, play a role in the regulation of other homing-associated molecules and thus enhance the inflammatory response. 9,10 Although VAP-1 has been known already for a long time and ...

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“…The cytosolic tails of most CD33-related Siglecs have two conserved tyrosine-based putative signaling motifs, one of which conforms to the immunoreceptor tyrosine-based inhibitory motif (ITIM), while the other is a putative motif of unknown function (1,9,10). It has been shown in some CD33-related Siglecs that the ITIM is the preferred docking site for the protein tyrosine phosphatase SHP-1 (27,32,36,41), and cross-linking of these Siglecs elicits negative signaling in the cells expressing these molecules (15,27,36,39,40). Although the expression pattern of CD33-related Siglecs and their function as signaling molecules suggest their involvement in the regulation of innate immunity, their in vivo function in a model organism has not been studied so far.…”

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confidence: 99%

CD33/Siglec-3 Binding Specificity, Expression Pattern, and Consequences of Gene Deletion in Mice

Linden¹,

Angata²,

Reynolds

et al. 2003

Molecular and Cellular Biology

103

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Mouse CD33/Siglec-3 (mCD33) is the apparent ortholog of human CD33/Siglec-3 (hCD33), a member of the Siglec (sialic acid-binding Ig superfamily lectin) family of sialic acid-recognizing cell-surface lectins. We examined the binding specificity and expression pattern of mCD33 and explored its functions by generating mice deficient in this molecule. Like hCD33, mCD33 is expressed on myeloid precursors in the bone marrow, albeit mostly in the more mature stages of the granulocytic lineage. Moreover, unlike hCD33, mCD33 in peripheral blood is primarily expressed on granulocytes. Also, unlike hCD33, mCD33 did not bind to ␣2-3-or ␣2-6-linked sialic acids on lactosamine units. Instead, it showed distinctive sialic acid-dependent binding only to the short O-linked glycans of certain mucins and weak binding to the sialyl-Tn epitope. Binding was enhanced by removal of 9-O-acetyl groups and attenuated by truncation of the glycerol-like side chain of sialic acids. Mice deficient in CD33 were viable and fertile in a controlled-access specific-pathogen-free vivarium, showed no major morphological or histological abnormalities, had no changes in bone marrow or peripheral leukocyte subpopulations, and had very minor differences in biochemical and erythrocyte parameters. Cellular responses to intraperitoneally injected proinflammatory stimulants, as well as subsequent interleukin-6 secretion, were also apparently unaffected. These results indicate substantial species differences in CD33 expression patterns and ligand recognition and suggest functional degeneracy between mCD33 and the other CD33-related Siglec proteins expressed on cells of the myeloid lineage.Human CD33 (hCD33) is an immunoglobulin (Ig) superfamily protein expressed on myeloid progenitor cells in the bone marrow and on peripheral blood monocytes. It is known to recognize ␣2-3-and ␣2-6-linked sialic acids (7, 18), which are expressed mostly at the nonreducing termini (outermost positions) of glycan chains (5, 38). Human CD33 (also known as hSiglec-3) is a member of the Siglec (sialic acid-binding Ig superfamily lectin) family of molecules defined by their mutual sequence similarity in the first two Ig-like domains and by their ability to recognize sialic acids (1, 9, 10;

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A new siglec family member, siglec‐10, is expressed in cells of the immune system and has signaling properties similar to CD33

Cited by 88 publications

References 39 publications

Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis

Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis

Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate

CD33/Siglec-3 Binding Specificity, Expression Pattern, and Consequences of Gene Deletion in Mice

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