title: Cholesterol-induced membrane microvesicles as novel carriers of damage-associated molecular patterns: mechanisms of formation, action, and detoxification.
abstract: OBJECTIVE
  Cholesterol enrichment occurs in vivo when phagocytes ingest retained and aggregated lipoproteins, damaged or senescent cells, and related debris. We previously reported that enrichment of human monocyte/macrophages with unesterified cholesterol (UC) triggers the release of highly procoagulant microvesicles ([MVs], also called microparticles) through induction of apoptosis. We determined whether UC-induced MVs (UCMVs) might transmit endogenous danger signals and, if so, what molecular processes might be responsible for their production, recognition, and detoxification.
  
  
  RESULTS
  Injection of UCMVs into rats provoked extensive leukocyte rolling and adherence to postcapillary venules in vivo. Likewise, exposure of mouse aortic explants or cultured human endothelial cells to UCMVs augmented the adhesion of human monocytes by several fold and increased endothelial cell intercellular adhesion molecule-1 via nuclear factor-κB activation. To explore molecular mechanisms, we found that UC enrichment of human monocytes, in the absence of other stimuli, induced mitochondrial complex II-dependent accumulation of superoxide and peroxides. A subset of these moieties was exported on UCMVs and mediated endothelial activation. Strikingly, aortic explants from mice lacking lectin-like oxidized low-density lipoprotein receptor-1, a pattern-recognition receptor, were essentially unable to respond to UCMVs, whereas simultaneously treated explants from wild-type mice responded robustly by increasing monocyte recruitment. Moreover, high-density lipoprotein and its associated enzyme paraoxonase-1 exerted unexpected roles in the detoxification of UCMVs.
  
  
  CONCLUSIONS
  Overall, our study implicates MVs from cholesterol-loaded human cells as novel carriers of danger signals. By promoting maladaptive immunologic and thrombotic responses, these particles may contribute to atherothrombosis and other conditions in vivo.
authors: Section of Endocrinology, Diabetes and Metabolism, Temple University School of Medicine, 3322 North Broad Street, Medical Office Building, room 212, Philadelphia, PA 19140, USA. Minglin.Liu@Temple.edu
authors: Ming-Lin
authors: ML
authors: Liu
authors: Rosario
authors: R
authors: Scalia
authors: Jawahar L
authors: JL
authors: Mehta
authors: Kevin Jon
authors: KJ
authors: Williams
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000008:administration & dosage / Q000378:metabolism*; D018920:Coculture Techniques; D042963:Electron Transport Complex II / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007275:Injections, Intravenous; D036904:Leukocyte Rolling; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051127:Scavenger Receptors, Class E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D046509:Tissue Culture Techniques; D014699:Venules / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C568779:ESAM protein, human; D000939:Epitopes; C428190:Esam protein, mouse; D016328:NF-kappa B; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E; D013481:Superoxides; D002784:Cholesterol; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C560867:PON1 protein, mouse