Targeting Siglecs with a sialic acid–decorated nanoparticle abrogates inflammation

Spence, Shaun; Greene, Michelle K.; Fay, François; Hams, Emily; Saunders, Sean P.; Hamid, Umar Imran; Fitzgerald, M; Beck, Jonathan; Bains, Baljinder Kaur; Smyth, Peter; Themistou, Efrosyni; Small, D.; Schmid, Daniela; O’Kane, Cecilia; Fitzgerald, Denise; Abdelghany, Sharif; Johnston, James A.; Fallon, Padraic G.; Burrows, James F.; McAuley, Daniel F.; Kissenpfennig, Adrien; Scott, Christopher J.

doi:10.1126/scitranslmed.aab3459

Cited by 145 publications

(101 citation statements)

References 53 publications

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“…In support of the regulatory function of siglecs, in most models tested, mice engineered to lack siglec-F exhibit exacerbated eosinophilic infiltration [64,65]. lung inflammation [68], and administration of siglec-E crosslinking sialylated nanoparticles reduces sepsis in mice [69]. Mice lacking siglec-E, considered an ortholog of siglec-9, have exacerbated neutrophil infiltration in bacterial lipopolysaccharide-induced Figure 9.…”

Section: Siglecs Regulate Inflammationmentioning

confidence: 97%

Glycobiology simplified: diverse roles of glycan recognition in inflammation

Schnaar

2016

Journal of Leukocyte Biology

109

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Glycans and complementary glycan-binding proteins are essential components in the language of cell-cell interactions in immunity. The study of glycan function is the purview of glycobiology, which has often been presented as an unusually complex discipline. In fact, the human glycome, composed of all of its glycans, is built primarily from only 9 building blocks that are combined by enzymes (writers) with specific and limited biosynthetic capabilities into a tractable and increasingly accessible number of potential glycan patterns that are functionally read by several dozen human glycan-binding proteins (readers). Nowhere is the importance of glycan recognition better understood than in infection and immunity, and knowledge in this area has already led to glycan mimetic anti-infective and anti-inflammatory drugs. This review includes a brief tutorial on human glycobiology and a limited number of specific examples of glycan-binding protein-glycan interactions that initiate and regulate inflammation. Examples include representatives from different glycan-binding protein families, including the C-type lectins (E-selectin, P-selectin, dectin-1, and dectin-2), sialic acid-binding immunoglobulin-like lectins (sialic acid-binding immunoglobulin-like lectins 8 and 9), galectins (galectin-1, galectin-3, and galectin-9), as well as hyaluronic acid-binding proteins. As glycoscience technologies advance, opportunities for enhanced understanding of glycans and their roles in leukocyte cell biology provide increasing opportunities for discovery and therapeutic intervention.

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Section: Siglecs Regulate Inflammationmentioning

confidence: 97%

Glycobiology simplified: diverse roles of glycan recognition in inflammation

Schnaar

2016

Journal of Leukocyte Biology

109

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“…Polyclonal Siglec-E antibody from R&D Systems (goat anti-Siglec-E) has been used in multiple studies (15)(16)(17). In a recent study, Siglec-E antibody was used to block the interaction of Siglec-E with sialylated ligands (18). In addition to antibodies that have been described in the literature, the ones that are commercially available include those from LifeSpan Biosciences (goat polyclonal Siglec-E and clone 8D2 rat monoclonal Siglec-E).…”

Section: Cd33-related Siglecs Are a Family Of Proteins Widely Expressmentioning

confidence: 99%

Studies on the Detection, Expression, Glycosylation, Dimerization, and Ligand Binding Properties of Mouse Siglec-E

Siddiqui

Schwarz

Springer

et al. 2017

Journal of Biological Chemistry

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Edited by Amanda F. Fosang CD33-related Siglecs are a family of proteins widely expressed on innate immune cells. Binding of sialylated glycans or other ligands triggers signals that inhibit or activate inflammation.Immunomodulation by Siglecs has been extensively studied, but relationships between structure and functions are poorly explored. Here we present new data relating to the structure and function of Siglec-E, the major CD33-related Siglec expressed on mouse neutrophils, monocytes, macrophages, and dendritic cells. We generated nine new rat monoclonal antibodies specific to mouse Siglec-E, with no cross-reactivity to Siglec-F. Although all antibodies detected Siglec-E on transfected human HEK-293T cells, only two reacted with mouse bone marrow neutrophils by flow cytometry and on spleen sections by immunohistochemistry. Moreover, whereas all antibodies recognized Siglec-E-Fc on immunoblots, binding was dependent on intact disulfide bonds and N-glycans, and only two antibodies recognized native Siglec-E within spleen lysates. Thus, we further investigated the impact of Siglec-E homodimerization. Homology-based structural modeling predicted a cysteine residue (Cys-298) in position to form a disulfide bridge between two Siglec-E polypeptides. Mutagenesis of Cys-298 confirmed its role in dimerization. In keeping with the high level of 9-O-acetylation found in mice, sialoglycan array studies indicate that this modification has complex effects on recognition by Siglec-E, in relationship to the underlying structures. However, we found no differences in phosphorylation or SHP-1 recruitment between dimeric and monomeric Siglec-E expressed on HEK293A cells. Phylogenomic analyses predicted that only some human and mouse Siglecs form disulfide-linked dimers. Notably, Siglec-9, the functionally equivalent human paralog of Siglec-E, occurs as a monomer. Two broad groups of Siglecs are identified based on their patterns of evolution. Sialoadhesin, CD22, myelin-associated glycoprotein (MAG) and Siglec-15 are highly conserved and show few changes among species (2). In contrast, CD33-related Siglecs evolve rapidly in mammals (2, 9). As there are not clear functional orthologs between primates and rodent Siglecs, these receptors are assigned an alphabetic letter in rodents and a number in primates. Siglec-E, the main CD33-related Siglec in mouse, was first discovered by a yeast two-hybrid screen using SHP-1 as a bait (10). Studies using a sheep polyclonal Siglec-E antibody specific for the ectodomain indicated that Siglec-E is expressed on neutrophils, macrophages, monocytes, dendritic cells, and a subset of Natural killer cells (11). The organ with the * This work was supported, in whole or in part, by National Institutes of Health Grants P01HL107150 and R01GM32373 (to A. V.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. □ S Th...

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“…Synthetic ligands that crosslink siglecs could include low-molecular weight compounds that contain at least two ligands, enabling them to crosslink larger molecules with many repeating ligands and even liposomes or nanoparticles that have on their surface siglec-binding ligands [26,60]. In all cases, the drugs should be highly specific for the desired siglec.…”

Section: Introductionmentioning

confidence: 99%

Regulation of airway inflammation by Siglec-8 and Siglec-9 sialoglycan ligand expression

Schleimer

Schnaar

Bochner

2016

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review Inflammatory cells involved in the allergic response, including eosinophils, mast cells, basophils, and neutrophils, express sialoglycan-binding proteins such as Siglec-8 and Siglec-9, which inhibit cell function and survival. The purpose of this review is to briefly discuss the biology of these siglecs and their ligands and consider their potential impact in pathology and treatment of chronic rhinosinusitis (CRS). Recent findings Recent studies demonstrate the presence of ligands for Siglec-8 and Siglec-9 in sinonasal tissue from patients with CRS as well as healthy patients, suggesting that the immunoregulatory functions of siglecs may be triggered in sinus tissue in health and disease. Summary Ligands for Siglec-8 and Siglec-9 may regulate the function of eosinophils, mast cells, neutrophils, and other cells in sinus mucosa. Therapeutic strategies that activate the anti-inflammatory effects of siglecs may dampen inflammation and disease in CRS patients.

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Targeting Siglecs with a sialic acid–decorated nanoparticle abrogates inflammation

Abstract: A nanoparticle coated with sialic acid activates Siglec receptors on macrophages, improving survival from sepsis in mice and reducing inflammation in human tissues.

Cited by 145 publications

References 53 publications

Glycobiology simplified: diverse roles of glycan recognition in inflammation

Glycobiology simplified: diverse roles of glycan recognition in inflammation

Studies on the Detection, Expression, Glycosylation, Dimerization, and Ligand Binding Properties of Mouse Siglec-E

Regulation of airway inflammation by Siglec-8 and Siglec-9 sialoglycan ligand expression

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