Microglial CD33-Related Siglec-E Inhibits Neurotoxicity by Preventing the Phagocytosis-Associated Oxidative Burst

Claude, Janine; Linnartz‐Gerlach, Bettina; Kudin, Alexei P.; Kunz, Wolfram S.; Neumann, Harald

doi:10.1523/jneurosci.2211-13.2013

Cited by 87 publications

(85 citation statements)

References 18 publications

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“…Previous studies reported that siglec receptors bound to a wide range of sialyloligosaccharides are important regulators of innate immunity [32]. SiglecE and H expressed in mouse microglia were demonstrated to modulate phagocytosis [33–35]. Therefore, we aimed to examine whether GLP modulated phagocytosis in BV2 and primary microglia was through siglec receptors.…”

Section: Resultsmentioning

confidence: 99%

Polysaccharides from Ganoderma lucidum attenuate microglia-mediated neuroinflammation and modulate microglial phagocytosis and behavioural response

Cai

Pei

2017

J Neuroinflammation

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Background Ganoderma lucidum (GL) has been widely used in Asian countries for hundreds of years to promote health and longevity. The pharmacological functions of which had been classified, including the activation of innate immune responses, suppression of tumour and modulation of cell proliferations. Effective fractions of Ganoderma lucidum polysaccharides (GLP) had already been reported to regulate the immune system. Nevertheless, the role of GLP in the microglia-mediated neuroinflammation has not been sufficiently elucidated. Further, GLP effect on microglial behavioural modulations in correlation with the inflammatory responses remains to be unravelled. The aim of this work was to quantitatively analyse the contributions of GLP on microglia.MethodsThe BV2 microglia and primary mouse microglia were stimulated by lipopolysaccharides (LPS) and amyloid beta42 (Aβ42) oligomer, respectively. Investigation on the effect of GLP was carried by quantitative determination of the microglial pro- and anti-inflammatory cytokine expressions and behavioural modulations including migration, morphology and phagocytosis. Analysis of microglial morphology and phagocytosis modulations was confirmed in the zebrafish brain.ResultsQuantitative results revealed that GLP down-regulates LPS- or Aβ-induced pro-inflammatory cytokines and promotes anti-inflammatory cytokine expressions in BV-2 and primary microglia. In addition, GLP attenuates inflammation-related microglial migration, morphological alterations and phagocytosis probabilities. We also showed that modulations of microglial behavioural responses were associated with MCP-1 and C1q expressions.ConclusionsOverall, our study provides an insight into the GLP regulation of LPS- and Aβ-induced neuroinflammation and serves an implication that the neuroprotective function of GLP might be achieved through modulation of microglial inflammatory and behavioural responses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0839-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Polysaccharides from Ganoderma lucidum attenuate microglia-mediated neuroinflammation and modulate microglial phagocytosis and behavioural response

Cai

Pei

2017

J Neuroinflammation

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“…Further studies are also needed to identify the putative sialic acid-modified ligands in human brain that activate CD33. Identifying these ligands might provide an approach to specifically targeting CD33 responses, though it needs to be appreciated that CD33 belongs to a related large family of sialic acid binding receptors (Siglecs), many of which have been shown also to be expressed by microglia (Claude et al, 2013;Linnartz and Neumann, 2013;Wang and Neumann, 2010). …”

Section: Discussionmentioning

confidence: 99%

Association of CD33 polymorphism rs3865444 with Alzheimer's disease pathology and CD33 expression in human cerebral cortex

Walker

Whetzel

Serrano

et al. 2015

Neurobiology of Aging

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Recent findings identified the minor A allele present in the single nucleotide polymorphism rs3865444 in the CD33 gene as being associated with reduced risk of developing Alzheimer’s disease (AD). CD33 (Siglec-3) is an immune function protein with anti-inflammatory signaling, cell adhesion and endocytosis functions with sialic acid-modified proteins or lipids as ligands. Its involvement in AD pathological mechanisms is still unclear, so the goal of this study was to investigate if the rs3865444 polymorphism affects development of AD pathology and the expression of CD33 mRNA and protein. For this study, we utilized DNA from 96 non-demented (ND) and 97 AD neuropathologically diagnosed cases to identify the different rs3865444 alleles and correlate with different measures of AD pathology. Using semi-quantitative histological measures of plaque and tangle pathology, we saw no significant differences between the different genotypes within these disease groups. However, increased expression of CD33 mRNA was associated with increasing AD pathology in temporal cortex brain samples. We also showed that cases with A/A alleles had reduced levels of CD33 protein in temporal cortex, but increased levels of the microglia protein IBA-1. Using immunohistochemistry on temporal cortex sections, CD33 was selectively localized to microglia, with greater expression in activated microglia. The factors causing increased CD33 expression by microglia in brain are still unclear, although both genetic and disease factors are involved. Treatment of human microglia isolated from autopsy brains with amyloid beta (Aβ) peptide and a range of other inflammatory activating agents resulted in reduced CD33 mRNA and protein levels.

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“…Later, a murine monoclonal antibody was used to detect Siglec-E followed by immunoprecipitation with an anti-phosphotyrosine antibody (4G10) (12). Some commercially available antibodies have been used to detect Siglec-E in transfected Chinese hamster ovary (CHO) cells (19) and mouse microglia (20). Polyclonal Siglec-E antibody from R&D Systems (goat anti-Siglec-E) has been used in multiple studies (15)(16)(17).…”

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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Microglial CD33-Related Siglec-E Inhibits Neurotoxicity by Preventing the Phagocytosis-Associated Oxidative Burst

Cited by 87 publications

References 18 publications

Polysaccharides from Ganoderma lucidum attenuate microglia-mediated neuroinflammation and modulate microglial phagocytosis and behavioural response

Polysaccharides from Ganoderma lucidum attenuate microglia-mediated neuroinflammation and modulate microglial phagocytosis and behavioural response

Association of CD33 polymorphism rs3865444 with Alzheimer's disease pathology and CD33 expression in human cerebral cortex

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

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