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Sialoadhesin, a macrophage sialic acid binding receptor for haemopoietic cells with 17 immunoglobulin-like domains.

ABSTRACT: Sialoadhesin is a macrophage-restricted adhesion molecule of 185 kDa that mediates sialic acid-dependent binding to cells. It is expressed strongly by macrophages in lymphoid and haemopoietic tissues where it is likely to mediate cell-cell interactions. Here we report the molecular cloning of murine sialoadhesin and show that it is a new member of the immunoglobulin (Ig) superfamily with 17 Ig-like domains. COS cells transfected with a cDNA encoding full-length sialoadhesin bound mouse bone marrow cells in a sialic acid-dependent manner. Alternatively spliced cDNAs, predicting soluble forms of sialoadhesin containing the first three or 16 Ig-like domains of sialoadhesin, were expressed in COS cells and the respective proteins purified. When immobilized on plastic, the 16-domain form bound cells in a sialic acid-dependent manner, suggesting that sialoadhesin can function in both secreted and membrane-bound forms. The most similar proteins in the database were CD22, myelin-associated glycoprotein, Schwann cell myelin protein and CD33. Like sialoadhesin, CD22 mediates sialic acid-dependent cell adhesion. The sequence similarity of sialoadhesin to CD22 and related members of the Ig superfamily indicates the existence of a novel family of sialic acid binding proteins involved in cell-cell interactions.

SUBMITTER: Crocker PR

PROVIDER: S-EPMC395382 | biostudies-other | 1994 Oct

REPOSITORIES: biostudies-other

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Sialoadhesin, a macrophage sialic acid binding receptor for haemopoietic cells with 17 immunoglobulin-like domains.

Crocker P R PR Mucklow S S Bouckson V V McWilliam A A Willis A C AC Gordon S S Milon G G Kelm S S Bradfield P P

The EMBO journal 19941001 19

Sialoadhesin is a macrophage-restricted adhesion molecule of 185 kDa that mediates sialic acid-dependent binding to cells. It is expressed strongly by macrophages in lymphoid and haemopoietic tissues where it is likely to mediate cell-cell interactions. Here we report the molecular cloning of murine sialoadhesin and show that it is a new member of the immunoglobulin (Ig) superfamily with 17 Ig-like domains. COS cells transfected with a cDNA encoding full-length sialoadhesin bound mouse bone marr ...[more]

PMID: 7925291

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Project description:Brain aging is a chronic process linked to inflammation, microglial activation, and oxidative damage, which can ultimately lead to neuronal loss. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a human lineage-specific microglial cell surface receptor that recognizes α-2-8-linked oligo-/polysialylated glycomolecules with inhibitory effects on the microglial inflammatory pathways. Recently, the SIGLEC11 gene locus was prioritized as a top tier microglial gene with potential causality to Alzheimer’s disease, although its role in inflammation and neurodegeneration remains poorly understood. In this study, aged Siglec-11 transgenic (tg) mice, which expressed the human SIGLEC-11 receptor on microglia and tissue macrophages, were investigated. The brains of the Siglec-11 tg mice were analyzed in 6-month-old mature mice and 24-month-old aged mice using immunohistochemistry and transcriptomics. Results showed decreased density and fewer clusters of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells in the hippocampus and substantia nigra, as well as less lipid-laden microglia in the Siglec-11 tg in comparison to wildtype (WT) controls. Additionally, Siglec-11 tg mice exhibited less age-related neuronal loss in the substantia nigra pars compacta in comparison to WT mice. Transcriptome analysis revealed suppression of oxidative phosphorylation and inflammatory pathways in Siglec-11 tg brains at 6 months, with further suppression of complement and coagulation cascades at 24 months of age in comparison to WT mice. Gene transcript levels of the pro-inflammatory cytokines tumor necrosis factor alpha (Tnf) and interleukin 1 beta (Il-1b), as well as the oxidative stress markers cytochrome b-245 alpha and beta (Cyba and Cybb) and the nitric oxide synthase 2 (Nos2) were reduced in the brains of 24-month-old Siglec-11 tg mice relative to WT controls. Brains of 24-month-old Siglec-11 tg mice also exhibited lower gene transcription of complement component 4 and integrin alpha M (C4 and Itgam), along with the complement C1q subcomponents a and c (C1qa and C1qc). In summary, aged Siglec-11 tg mice displayed reduced brain inflammation and oxidative stress, as well as protection against age-related neuronal loss in the substantia nigra.

Project description:BACKGROUND:Siglec-8 is a CD33 subfamily cell-surface receptor selectively expressed on human eosinophils. After cytokine priming, Siglec-8 mAb or glycan ligand binding causes eosinophil apoptosis associated with reactive oxygen species (ROS) production. Most CD33-related Siglecs function as inhibitory receptors, but the ability of Siglec-8 to stimulate eosinophil ROS production and apoptosis suggests that Siglec-8 might instead function as an activating receptor. OBJECTIVE:We sought to determine the role of IL-5 priming and identify the signaling molecules involved in Siglec-8 function for human eosinophils. METHODS:We used an mAb and/or a multimeric synthetic sulfated sialoglycan ligand recognizing Siglec-8 in combination with integrin blocking antibodies, pharmacologic inhibitors, phosphoproteomics, and Western blot analysis to define the necessity of various proteins involved in Siglec-8 function for human eosinophils. RESULTS:Cytokine priming was required to elicit the unanticipated finding that Siglec-8 engagement promotes rapid ?2-integrin-dependent eosinophil adhesion. Also novel was the finding that this adhesion was necessary for subsequent ROS production and apoptosis. Siglec-8-mediated ROS was generated through reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation because pretreatment of eosinophils with catalase (an extracellular superoxide scavenger) or NSC 23766 (a Rac GTPase inhibitor) completely inhibited Siglec-8-mediated eosinophil apoptosis. Finally, engagement of Siglec-8 on IL-5-primed eosinophils resulted in increased phosphorylation of Akt, p38, and c-Jun N-terminal kinase 1 that was also ?2-integrin dependent; pharmacologic inhibition of these kinases completely prevented Siglec-8-mediated eosinophil apoptosis. CONCLUSIONS:These data demonstrate that Siglec-8 functions uniquely as an activating receptor on IL-5-primed eosinophils through a novel pathway involving regulation of ?2-integrin-dependent adhesion, NADPH oxidase, and a subset of protein kinases.

Dataset Information

Sialoadhesin, a macrophage sialic acid binding receptor for haemopoietic cells with 17 immunoglobulin-like domains.

Publications

Sialoadhesin, a macrophage sialic acid binding receptor for haemopoietic cells with 17 immunoglobulin-like domains.

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