Alleviation of neurotoxicity by microglial human Siglec-11.
Sialic acid-binding Ig superfamily lectins (Siglecs) are members of the Ig superfamily that recognize sialic acid residues of glycoproteins. Siglec-11 is a recently identified human-specific CD33-related Siglec that binds to alpha2,8-linked polysialic acids and is expressed on microglia, the brain resident innate immune cells. Polysialylated neuronal cell adhesion molecule (PSA-NCAM) is a putative ligand of Siglec-11. We observed gene transcription and protein expression of Siglec-11 splice variant 2 in human brain tissue samples by RT-PCR and Western blot analysis. Siglec-11 was detected on microglia in human brain tissue by immunohistochemistry. Human Siglec-11 splice variant 2 was ectopically expressed by a lentiviral vector system in cultured murine microglial cells. Stimulation of Siglec-11 by cross-linking suppressed the lipopolysaccharides (LPS)-induced gene transcription of the proinflammatory mediators interleukin-1beta and nitric oxide synthase-2 in microglia. Furthermore, phagocytosis of apoptotic neuronal material was reduced in Siglec-11 transduced microglia. Expression of PSA-NCAM was detected on microglia and neurons by immunohistochemistry and RT-PCR. Coculture of microglia transduced with Siglec-11 and neurons demonstrated neuroprotective function of Siglec-11. The neuroprotective effect of Siglec-11 was dependent on polysialic acid (PSA) residues on neurons, but independent on PSA on microglia. Thus, data demonstrate that human Siglec-11 ectopically expressed on murine microglia interacts with PSA on neurons, reduces LPS-induced gene transcription of proinflammatory mediators, impairs phagocytosis and alleviates microglial neurotoxicity.
Wang
Yiner
Y
Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, Bonn, Germany.
Neumann
Harald
H
D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D018920:Coculture Techniques; D019610:Cytoprotection / Q000502:physiology; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005822:Genetic Vectors; D005911:Gliosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012794:Sialic Acids / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
D018836:Inflammation Mediators; D037102:Lectins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D039842:Neural Cell Adhesion Molecule L1; D020033:Protein Isoforms; D012333:RNA, Messenger; C464442:SIGLEC11 protein, human; D012794:Sialic Acids; C021319:polysialic acid; C103469:polysialyl neural cell adhesion molecule