title: Macrophage recognition of toxic advanced glycosylation end products through the macrophage surface-receptor nucleolin.
abstract: Advanced glycosylation end-products (AGEs) are non-enzymatically glycosylated proteins that play an important role in several diseases and aging processes, including angiopathy, renal failure, diabetic complications, and some neurodegenerative diseases. In particular, glyceraldehyde (GCA)- and glycolaldehyde (GOA)-derived AGEs are deemed toxic AGEs, due to their cytotoxicity. Recently, the shuttling-protein nucleolin has been shown to possess scavenger receptor-activity. Here, we investigated whether or not macrophages recognize toxic AGEs through nucleolin receptors expressed on their surface. Free amino acid groups and arginine residues found in bovine serum albumin (BSA) were time-dependently modified by incubation with GCA and GOA. In addition, average molecular size was increased by incubation with GCA and GOA. While GCA-treated BSA (GCA-BSA) and GOA-treated BSA (GOA-BSA) were recognized by thioglycollate-elicited mouse peritoneal macrophages in proportion to their respective aldehyde-modification ratios, aldehyde-untreated control-BSA was not. Surface plasmon-resonance analysis revealed that nucleolin strongly associated with GCA-BSA and GOA-BSA, but not with control-BSA. Further, pretreating macrophages with anti-nucleolin antibody, but not control-Immunoglobulin G, inhibited recognition of GCA-BSA and GOA-BSA by macrophages. Additionally, AGRO, a nucleolin-specific oligonucleotide aptamer, inhibited recognition of GCA-BSA and GOA-BSA. Moreover, nucleolin-transfected HEK293 cells recognized more GCA-BSA and GOA-BSA than control HEK cells did. Binding of nucleolin and GCA-BSA/GOA-BSA was also blocked by anti-nucleolin antibody at molecular level. These results indicate that nucleolin is a receptor that allows macrophages to recognize toxic AGEs.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Miki
authors.forename: Hikaru
authors.initials: H
authors.lastname: Dambara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tachibana
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hirano
authors.forename: Mio
authors.initials: M
authors.lastname: Konishi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Beppu
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D052157:Aptamers, Nucleotide; D002417:Cattle; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D005985:Glyceraldehyde / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014162:Transfection; D000097796:Nucleolin
chemical_list: D000079:Acetaldehyde; D052157:Aptamers, Nucleotide; D017127:Glycation End Products, Advanced; D005985:Glyceraldehyde; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D012710:Serum Albumin, Bovine; D000097796:Nucleolin; C513936:AGRO 100; C010972:glycolaldehyde