Abstract
Both pathogen- and tissue damage-associated molecular patterns induce inflammation through toll-like receptors (TLRs), while sialic acid-binding immunoglobulin superfamily lectin receptors (Siglecs) provide negative regulation. Here we report extensive and direct interactions between these pattern recognition receptors. The promiscuous TLR binders were human SIGLEC-5/9 and mouse Siglec-3/E/F. Mouse Siglec-G did not show appreciable binding to any TLRs tested. Correspondingly, Siglece deletion enhanced dendritic cell responses to all microbial TLR ligands tested, while Siglecg deletion did not affect the responses to these ligands. TLR4 activation triggers Neu1 translocation to cell surface to disrupt TLR4:Siglec-E interaction. Conversely, sialidase inhibitor Neu5Gc2en prevented TLR4 ligand-induced disruption of TLR4:Siglec E/F interactions. Absence of Neu1 in hematopoietic cells or systematic treatment with sialidase inhibitor Neu5Gc2en protected mice against endotoxemia. Our data raised an intriguing possibility of a broad repression of TLR function by Siglecs and a sialidase-mediated de-repression that allows positive feedback of TLR activation during infection.
Keywords:
E. coli; Siglec; immunology; mouse; sialidase; toll-like receptor.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology*
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Antigens, CD / metabolism
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / immunology*
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Antigens, Differentiation, B-Lymphocyte / metabolism
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Cell Line
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Cytokines / immunology
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Cytokines / metabolism
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Dendritic Cells / drug effects
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Endotoxemia / immunology
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Endotoxemia / microbiology
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Endotoxemia / prevention & control
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Enzyme Inhibitors / immunology
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Enzyme Inhibitors / pharmacology
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Humans
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Immunoblotting
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Lipopolysaccharides / immunology
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Lipopolysaccharides / pharmacology
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Fluorescence
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Neuraminidase / genetics
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Neuraminidase / immunology*
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Neuraminidase / metabolism
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Oligodeoxyribonucleotides / immunology
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Oligodeoxyribonucleotides / pharmacology
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Protein Binding
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Protein Isoforms / genetics
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Protein Isoforms / immunology
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Protein Isoforms / metabolism
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Receptors, Pattern Recognition / genetics
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Receptors, Pattern Recognition / immunology*
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Receptors, Pattern Recognition / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology*
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Toll-Like Receptor 4 / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation, B-Lymphocyte
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Cytokines
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Enzyme Inhibitors
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Lipopolysaccharides
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Oligodeoxyribonucleotides
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Protein Isoforms
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Receptors, Pattern Recognition
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Siglece protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Neu1 protein, mouse
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Neuraminidase