title: Vimentin is an endogenous ligand for the pattern recognition receptor Dectin-1.
abstract: OBJECTIVE
  Atherosclerosis is a chronic inflammatory disorder of cholesterol deposition in monocyte-derived macrophages (MDM) within the arterial wall leading to impingement on the lumen of the vessel. In atherosclerotic lesions, MDM are the primary source of NADPH oxidase-derived superoxide anion (O₂⁻) inducing low-density lipoprotein (LDL) oxidation leading to their unregulated uptake of oxidized LDL and foam cell formation. We recently discovered that zymosan potently activates monocyte NADPH oxidase via the non-toll pattern recognition receptor (PRR), Dectin-1. Other PRRs bind endogenous human ligands, yet no such ligands have been identiﬁed for Dectin-1. Our hypothesis was that inﬂammation generates endogenous ligands for Dectin-1 that activate O₂⁻ production and thereby contributes to atherogenesis.
  
  
  RESULTS
  Human: anti-zymosan antibodies were used to identify similar, cross-reactive epitopes in human atherosclerotic tissue extracts. Immunoblot analysis revealed consistent antibody reactive protein bands on one- and two-dimensional gel electrophoreses. Vimentin was identified by mass spectrometry in the immunoreactive bands across different tissue samples. Direct binding of vimentin to Dectin-1 was observed using BIACORE. Further data revealed that vimentin induces O₂⁻ production by human monocytes. Analysis of human atherosclerotic lesions revealed that vimentin was detected extracellularly in the necrotic core and in areas of active inflammation. Vimentin also co-localized with Dectin-1 in macrophage-rich regions where O₂⁻ is produced.
  
  
  CONCLUSIONS
  We conclude that vimentin is an endogenous, activating ligand for Dectin-1. Its presence in areas of artery wall inflammation and O₂⁻ production suggests that vimentin activates Dectin-1 and contributes to the oxidation of lipids and cholesterol accumulation in atherosclerosis.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA.
authors.forename: Praveena S
authors.initials: PS
authors.lastname: Thiagarajan
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.forename: Deena H
authors.initials: DH
authors.lastname: Elsori
authors.forename: Satya P
authors.initials: SP
authors.lastname: Yadav
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.forename: Carmela D
authors.initials: CD
authors.lastname: Tan
authors.forename: E René
authors.initials: ER
authors.lastname: Rodriguez
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Martha K
authors.initials: MK
authors.lastname: Cathcart
mesh_terms: D016893:Carotid Stenosis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D015151:Immunoblotting; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*; D015054:Zymosan / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D002784:Cholesterol; D037181:Lectins, C-Type; D008024:Ligands; D051192:Receptors, Pattern Recognition; D013481:Superoxides; D014746:Vimentin; D015054:Zymosan; C546929:CLEC7A protein, human; D000099181:Dectin-1
keywords: Alarmins; Atherosclerosis; Dectin-1; Extracellular vimentin; Superoxide anion