SIGLEC8

Last updated
SIGLEC8
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SIGLEC8 , SAF2, SIGLEC-8, SIGLEC8L, sialic acid binding Ig like lectin 8
External IDs OMIM: 605639 MGI: 2681107 HomoloGene: 50482 GeneCards: SIGLEC8
Orthologs
SpeciesHumanMouse
Entrez

27181

233186

Ensembl

ENSG00000105366

ENSMUSG00000039013

UniProt

Q9NYZ4

Q920G3

RefSeq (mRNA)

NM_014442
NM_001363548

NM_001271019
NM_145581

RefSeq (protein)

NP_055257
NP_001350477

NP_001257948
NP_663556

Location (UCSC) Chr 19: 51.45 – 51.46 Mb Chr 7: 43 – 43.01 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Sialic acid-binding Ig-like lectin 8 is a protein that in humans is encoded by the SIGLEC8 gene. [5] [6] This gene is located on chromosome 19q13.4, about 330 kb downstream of the SIGLEC9 gene. [5] [7] Within the siglec family of transmembrane proteins, Siglec-8 belongs to the CD33-related siglec subfamily, a subfamily that has undergone rapid evolution. [8] [9] [10]

Contents

Initial characterization

Siglec-8 was first identified by CD33 homology screening of ESTs from a cDNA library generated from a patient diagnosed with idiopathic hypereosinophilic syndrome and was originally termed SAF-2 (sialoadhesin family 2). [5] [8] At the tissue level, Siglec-8 mRNA was found to be most highly expressed in lung, PBMCs, spleen, and kidney. [8]

Expression

Siglec-8 is expressed by human eosinophils, mast cells, and, to a lesser extent, basophils. [8] It has thus garnered attention as a molecule that is uniquely expressed by immune effector cells involved in asthma and allergy. In both eosinophils and mast cells, Siglec-8 is expressed late in development. Siglec-8 transcript and protein are detectable at day 12 during the in vitro differentiation of eosinophils from cord blood precursors, whereas the transcription factor GATA-1 peaks at day 2 and the secondary granule protein MBP-1 peaks at day 4 in this differentiation system. [11] [12] In mast cells generated from CD34+ precursors, Siglec-8 expression peaks at 4 weeks of differentiation, in parallel with FcεRIα surface expression. [13]

Consistent with the concept that Siglec-8 is a late differentiation marker, Siglec-8 has not been detected on the surface of relatively undifferentiated eosinophilic cell lines, such as EoL-1, AML14, AML14.3D10, or K562, the basophilic leukemia cell line KU812, nor on cells such as HL60 or EoL-3 that have been differentiated towards an eosinophil-like lineage. [8] [11] Only low levels are detected on the human mast cell sub-line HMC-1.1; however, the HMC-1.2 cell line, which bears a second KIT mutation (D816V, in addition to the V560G mutation found in both HMC-1.1 and HMC-1.2 cells) that may induce further differentiation, expresses Siglec-8 at the cell surface. [11] However, based on a small sampling of patients, all eosinophils from patients with chronic eosinophilic leukemia (CEL), hypereosinophilic syndrome, or chronic myeloid leukemia (CML), all basophils from patients with CEL or CML, and all bone marrow mast cells from patients with indolent systemic mastocytosis or aplastic anemia express Siglec-8, providing a potential target for these cells in the context of these hematologic malignancies. [11]

In addition, baboon eosinophils as well as monocytes, a subset of lymphocytes, and neutrophils express on their cell surface a protein or proteins that are recognized by polyclonal human Siglec-8-specific antibody, consistent with genetic analyses indicating the existence of a Siglec-8 ortholog in this species. [9] [11] However, the 2C4, 2E2, and 7C9 monoclonal antibodies against human Siglec-8 were not found to bind to targets on baboon cells, indicating that these particular epitopes are not conserved. [11]

Structure

Two splice variants of Siglec-8 exist. [7] The initially characterized form contains 431 amino acid residues in total, 47 of which comprise an uncharacteristically short cytoplasmic tail compared to most CD33-associated siglecs. Subsequently, a longer form of Siglec-8, initially termed Siglec-8L, that contains 499 amino acid residues was identified. This longer form of Siglec-8 shares the same extracellular region but includes a longer cytoplasmic tail with two tyrosine-based motifs (an immunoreceptor tyrosine-based inhibitory motif [ITIM] and an immunoreceptor tyrosine-based switch motif [ITSM]). Both forms of Siglec-8 are found in eosinophils and contain a V-set domain with lectin activity and two C2-type Ig repeat domains in the extracellular region. [14] Given that the longer version is felt to be the normal version, the term Siglec-8 is best used to refer to the 499 amino acid version, while the 431 amino acid version is best referred to as the “short form” of Siglec-8.

Ligand binding

Potential glycan ligands for Siglec-8 have been screened by glycan array. [15] [16] The glycan NeuAcα2–3(6-O-sulfo)Galβ1–4[Fucα1–3]GlcNAc, also known as 6′-sulfo-sialyl Lewis X, binds with high affinity to both Siglec-8 and to a mouse siglec, Siglec-F, which appears to have acquired a similar but not identical function and pattern of expression to human Siglec-8 through convergent evolution (the two siglecs are not orthologous). [15] [16] Rescreening on a more expanded glycan array reconfirmed this finding, but also identified a second closely related ligand in which the fucose is absent (NeuAcα2–3(6-O-sulfo)Galβ1–4GlcNAc, or 6′-sulfated sialyl N-acetyl-D-lactosamine. [17] These interactions are quite specific; no binding could be detected between these siglecs and unsulfated sialyl Lewis X or sialyl Lewis X sulfated at carbon 6 of GlcNAc (6-sulfo-sialyl Lewis X) rather than carbon 6 of galactose as in 6′-sulfo-sialyl Lewis X. Similarly, no other siglecs bind effectively to these Siglec-8 ligands, as demonstrated by selective binding to eosinophils in human blood of a polymer decorated with 6′-sulfo-sialyl Lewis X. The natural ligand or ligands for Siglec-8 have not yet been positively identified, but ongoing studies have determined that there are sialidase-sensitive glycoprotein ligands for Siglec-F in mouse airways that require the activity of the α2,3 sialyltransferase 3 (ST3Gal-III) enzyme for their generation. [17] [18] [19]

There is also evidence that Siglec-8 on eosinophils interacts with sialylated cis ligands. Treatment of human eosinophils with sialidase increases the extent to which a high-avidity glycan ligand (1-MDa polyacrylamide ribbon decorated with 6′-O-sulfo-3′-sialyl-LacNAc) binds to these cells by about 50%. [20] Indeed, removal of α2,3-linked sialic acid from the cell surface not only enables Siglec-8 to bind ligand in trans to a greater extent (i.e., unmasks Siglec-8) but also impacts Siglec-8 function upon antibody engagement, which itself is not impeded by Siglec-8 interactions with cis ligands. [21] The precise identities of the glycan ligands to which Siglec-8 binds in cis or the carrier molecules bearing them have not been determined.

Signaling and function

Eosinophils

Consistent with the role of most siglecs and the presence of the intracellular ITIM, Siglec-8 has been found to function as an inhibitory immunoregulatory receptor. Ligation of Siglec-8 induces cell death in eosinophils, and, surprisingly, the normally pro-survival cytokines interleukin (IL)-5 and GM-CSF have been found to potentiate this cell death effect. [22] IL-33, which activates and maintains eosinophils, also exerts a similar potentiating effect on Siglec-8-induced cell death. [23] [24] [25] Inhibitor studies demonstrate that cell death induced by crosslinking Siglec-8 through the use of an anti-Siglec-8 mAb and a secondary antibody is mediated sequentially through reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and caspase activation. [26] In the presence of IL-5, the loss of mitochondrial membrane integrity is accelerated and the secondary crosslinking antibody is no longer necessary to induce cell death. [27] IL-5 stimulation also appears to alter the mode of cell death of eosinophils induced by Siglec-8 ligation in that cell death becomes a caspase-independent process. On IL-5-primed eosinophils, antibody ligation of Siglec-8 was found to lead to CD11b/CD18 integrin upregulation, conformational activation, and subsequent integrin-mediated adhesion. [28] Disruption of integrin-mediated adhesion with antibodies to CD18 prevented Siglec-8-induced ROS production and cell death, indicating that β2 integrins act as essential mediators in the Siglec-8 ligation-induced cell death process in eosinophils. [28] The signaling cascade leading to CD11b/CD18 integrin upregulation and conformational activation was elucidated using pharmacologic inhibition of key signaling molecules combined with analyses of cellular events leading to cell death. [29] This signaling pathway is atypical for an ITIM-bearing siglec and involves the activities of a Src family kinase, Syk, PI3K, phospholipase C, protein kinase C, Rac1, PAK1, MEK1, and ERK1/2. [29] The conformational activation of CD11b was dependent on the activity of Bruton's tyrosine kinase. There was no evidence supporting the involvement of protein tyrosine phosphatases typically associated with ITIM-mediated signaling pathways, such as SHP-1/2, in this pathway. [29]

Disruption of Siglec-8 binding to α2,3-sialylated cis ligands enables Siglec-8 engagement-induced cell death in eosinophils and overcomes the need for cytokine priming (e.g. , with IL-5, GM-CSF, or IL-33) or extensive receptor cross-linking. [21] The cell death pathway licensed by enzymatic removal of these sialylated cis ligands resembles that described in eosinophils primed with IL-5 in that it involves cell-surface upregulation of CD11b and ROS production and requires the activities of Syk, PI3K, and phospholipase C.

Concurrent stimulation of the IL-5 receptor and Siglec-8 leads to a type of cell death resembling regulated necrosis that is promoted by MEK1/ERK signaling. [30] In this experimental system, inhibition of MEK1 does not alter ROS generation but the ROS inhibitor diphenyleneiodonium inhibits ERK1/2 phosphorylation and cell death, leading to the conclusion that the production of ROS is upstream of MEK1/ERK signaling in this pathway. [30] However, in eosinophils that had been primed with IL-5 18–24 h prior to Siglec-8 ligation, the activities of MEK1 and ERK1/2 are necessary prior to integrin upregulation and ROS production. [29] Cell death induced by Siglec-8 in the presence of IL-33, in contrast, is mediated primarily by a caspase-dependent pathway, and IL-33 is capable of synergizing with IL-5 in potentiating cell death induced by Siglec-8 ligation. [24]

Siglec-8 undergoes endocytosis upon antibody ligation on eosinophils and mast cells. [20] This process is dependent on the cytoplasmic ITIM (and not the ITSM), the activities of tyrosine kinases and protein kinase C, and actin rearrangement. Furthermore, it can be exploited to deliver toxins to human eosinophils or mast cells to selectively induce cell death when Siglec-8 ligation by itself would not be sufficient to do so (e.g., on mast cells or unprimed eosinophils). [20]

Mast cells and basophils

Siglec-8 antibody engagement has been shown to inhibit FcεRIα-mediated Ca2+ flux and release of prostaglandin D2 and histamine. [31] In experiments using the rat basophilic leukemia cell line RBL-2H3 stably transfected with Siglec-8, the inhibitory effect of Siglec-8 ligation on FcεRIα-mediated degranulation and Ca2+ flux was found to be dependent on the intact ITIM. [31] In studies involving transgenic mouse Siglec-8-expressing bone marrow-derived mast cells, co-engagement of Siglec-8 and FcεRIα leads to the inhibition of proximal kinase signaling downstream of FcεRI ligation. [32] However, the inhibitory activity of Siglec-8 extends beyond counteracting FcεRI-mediated mast cell activation in transgenic mice: monoclonal antibody engagement of Siglec-8 reduced mast cell activation, immune cell recruitment, and lung fibrosis in a cigarette smoke-induced model of chronic obstructive pulmonary disease and in a bleomycin-induced model of lung injury. [33] Antibody engagement of Siglec-8 also impeded IL-33-driven mast cell activation and immune cell recruitment. Unlike on eosinophils, antibody engagement of Siglec-8 on human mast cells does not lead to substantial levels of cell death. However, enzymatic removal of α2,3-linked sialic acid from the cell surface promotes cell death upon Siglec-8 antibody ligation on primary human mast cells, suggesting that this pathway remains intact in mast cells but that it is restrained by the interaction of Siglec-8 with cis ligands. [21]

There are no published data regarding the function of Siglec-8 on basophils.

Relationships with other siglecs

Due to its high level of sequence homology with CD33 (Siglec-3), Siglec-8 is grouped within the CD33-related siglec subfamily. This family is composed of a rapidly evolving group of siglecs that share 50–99% sequence identity. [34] Most members of the subfamily also possess conserved cytoplasmic ITIM and ITIM-like sequences.

Mouse Siglec-F

While SIGLEC8 and mouse Siglecf do not appear to derive from the same ancestral gene (they are paralogous, not orthologous), they share a binding preference for 6′-sulfo-sialyl Lewis X and 6′-sulfated sialyl N-acetyl-D-lactosamine, similar but distinct patterns of cellular expression, and similar inhibitory functions. For example, Siglec-F is expressed by eosinophils, like Siglec-8, but is also expressed by alveolar macrophages and has not been detected on mouse mast cells or basophils. [35] [36] [37] This functional convergence of Siglec-8 and Siglec-F has permitted in vivo studies to be performed in mouse models of eosinophil-mediated disorders that may provide information about the human system. In a chicken ovalbumin (OVA) model of allergic airway inflammation, the Siglec-F knockout mouse exhibits increased lung eosinophilia, enhanced inflammation, delayed resolution, and exacerbated peribronchial fibrosis. [36] [38] Antibody ligation of Siglec-F has also been shown to inhibit eosinophil-mediated intestinal inflammation and airway remodeling in OVA challenge models. [39] [40] The ST3Gal-III enzyme is necessary for the generation of the natural Siglec-F ligand, which remains unknown but is induced by IL-4 and IL-13 in the airway. [17] [19] [38] Loss of this enzyme leads to enhanced allergic eosinophilic airway inflammation. [17] [19] Despite evidence that Siglec-F binds specifically to 6′-sulfo-sialyl Lewis X and 6′-sulfated sialyl N-acetyl-D-lactosamine, in which galactose is sulfated at carbon 6, mice deficient in the two known galactose 6-O-sulfotransferases, keratan sulfate galactose 6-O-sulfotransferase (KSGal6ST) and chondroitin 6-O-sulfotransferase 1 (C6ST-1), express equivalent levels of Siglec-F ligand. [15] [16] [41] These models may shed some light on the regulation of human eosinophil biology by Siglec-8 and the production of natural Siglec-8 ligands in humans. Also like Siglec-8, Siglec-F ligation leads to the apoptosis of eosinophils. [36] [37] However, Siglec-F–induced eosinophil apoptosis is mediated by a mechanism distinct from that employed by Siglec-8, hindering direct comparisons between the mouse and human systems. Siglec-F-induced apoptosis is mediated by caspase activation in mouse eosinophils and does not involve ROS, in contrast to the mechanism reported in Siglec-8–induced apoptosis of human eosinophils. [42] This apoptotic mechanism also does not involve Src family kinases, SHP-1, or NADPH. [42]

Clinical trials

In a randomized clinical trial, lirentelimab, a monoclonal antibody targeting SIGLEC8 has been evaluated as a treatment for eosinophilic gastritis and duodenitis. [43]

Related Research Articles

<span class="mw-page-title-main">Eosinophil</span> Variety of white blood cells

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply. They form about 2 to 3% of white blood cells in the body.

<span class="mw-page-title-main">Eosinophilia</span> Blood condition

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

<span class="mw-page-title-main">Basophil</span> Type of white blood cell

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte and how they work is not fully understood. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues, but they are now known to be different types of cells.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Selectin</span> Family of cell adhesion molecules

The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.

Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells and mast cells.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">P-selectin</span> Type-1 transmembrane protein

P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.

<span class="mw-page-title-main">Eosinophilic esophagitis</span> Allergic inflammatory condition of the esophagus

Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In healthy individuals, the esophagus is typically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartburn.

<span class="mw-page-title-main">FCER1</span>

The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in allergy disorders and parasite immunity. FcεRI is a tetrameric receptor complex that binds Fc portion of the ε heavy chain of IgE. It consists of one alpha, one beta, and two gamma chains connected by two disulfide bridges on mast cells and basophils. It lacks the beta subunit on other cells. It is constitutively expressed on mast cells and basophils and is inducible in eosinophils.

<span class="mw-page-title-main">E-selectin</span>

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

<span class="mw-page-title-main">Interleukin 25</span> Cytokine that belongs to the IL-17 cytokine family

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E) – is a protein that in humans is encoded by the IL25 gene on chromosome 14. IL-25 was discovered in 2001 and is made up of 177 amino acids.

Siglecs(Sialic acid-binding immunoglobulin-type lectins) are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. There are 14 different mammalian Siglecs, providing an array of different functions based on cell surface receptor-ligand interactions.

OX40L is the ligand for OX40 and is stably expressed on many antigen-presenting cells such as DC2s, macrophages, and activated B lymphocytes.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

<span class="mw-page-title-main">Eosinophil cationic protein</span> Mammalian protein found in Homo sapiens

Eosinophil cationic protein (ECP) also known as ribonuclease 3 is a basic protein located in the eosinophil primary matrix. In humans, the eosinophil cationic protein is encoded by the RNASE3 gene.

<span class="mw-page-title-main">SIGLEC7</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 7 is a protein that in humans is encoded by the SIGLEC7 gene. SIGLEC7 has also been designated as CD328.

Lymphocyte-variant hypereosinophilia is a rare disorder in which eosinophilia or hypereosinophilia is caused by an aberrant population of lymphocytes. These aberrant lymphocytes function abnormally by stimulating the proliferation and maturation of bone marrow eosinophil-precursor cells termed colony forming unit-eosinophils or CFU-Eos.

Lirentelimab is a humanized nonfucosylated monoclonal antibody that targets sialic acid-binding Ig-like lectin 8 (SIGLEC8). In a randomized clinical trial, lirentelimab was found to improve eosinophil counts and symptoms in individuals with eosinophilic gastritis and duodenitis. Adverse reactions include infusion reactions, which are mild to moderate and typically occur following the first infusion.

<span class="mw-page-title-main">SIGLEC6</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 6 is a protein that in humans is encoded by the SIGLEC6 gene. The gene was originally named CD33L (CD33-like) due to similarities between these genes but later became known as OB-BP1 due to its ability to bind to this factor and, finally, SIGLEC6 as the sixth member of the SIGLEC family of receptors to be identified. The protein has also been given the CD designation CD327.

References

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