title: Reconstituted High-Density Lipoprotein Attenuates Cholesterol Crystal-Induced Inflammatory Responses by Reducing Complement Activation.
abstract: Chronic inflammation of the arterial wall is a key element in the development of atherosclerosis, and cholesterol crystals (CC) that accumulate in plaques are associated with initiation and progression of the disease. We recently revealed a link between the complement system and CC-induced inflammasome caspase-1 activation, showing that the complement system is a key trigger in CC-induced inflammation. HDL exhibits cardioprotective and anti-inflammatory properties thought to explain its inverse correlation to cardiovascular risk. In this study, we sought to determine the effect of reconstituted HDL (rHDL) on CC-induced inflammation in a human whole blood model. rHDL bound to CC and inhibited the CC-induced complement activation as measured by soluble terminal C5b-9 formation and C3c deposition on the CC surface. rHDL attenuated the amount of CC-induced complement receptor 3 (CD11b/CD18) expression on monocytes and granulocytes, as well as reactive oxygen species generation. Moreover, addition of CC to whole blood resulted in release of proinflammatory cytokines that were inhibited by rHDL. Our results support and extend the notion that CC are potent triggers of inflammation, and that rHDL may have a beneficial role in controlling the CC-induced inflammatory responses by inhibiting complement deposition on the crystals.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Niyonzima
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway; Department of Medicine, Ålesund Hospital, Ålesund 6026, Norway;
authors.forename: Eivind O
authors.initials: EO
authors.lastname: Samstad
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway;
authors.forename: Marie H
authors.initials: MH
authors.lastname: Aune
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway;
authors.forename: Liv
authors.initials: L
authors.lastname: Ryan
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway;
authors.forename: Siril S
authors.initials: SS
authors.lastname: Bakke
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway; Central Norway Regional Health Authority, Trondheim N-7501, Norway;
authors.forename: Anne Mari
authors.initials: AM
authors.lastname: Rokstad
authors.affiliation: Cardiovascular Therapeutics, CSL Behring, King of Prussia, PA 19406;
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway;
authors.forename: Jan K
authors.initials: JK
authors.lastname: Damås
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway; Department of Immunology, Oslo University Hospital, Oslo N-0027, Norway; K.G. Jebsen Inflammatory Research Centre, University of Oslo, Oslo N-0027, Norway; Research Laboratory, Nordland Hospital, Bodø N-8092, Norway; K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø N-9037, Norway; and.
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway; Biomedical Center, Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway; terje.espevik@ntnu.no.
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
mesh_terms: D001773:Blood Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology; D018821:CD18 Antigens / Q000276:immunology; D002784:Cholesterol / Q000009:adverse effects*; D003167:Complement Activation / Q000187:drug effects*; D015932:Complement C3c / Q000037:antagonists & inhibitors / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors / Q000276:immunology; D003460:Crystallization; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D015938:Complement Membrane Attack Complex; C509295:ITGAM protein, human; D008075:Lipoproteins, HDL; D017382:Reactive Oxygen Species; D015932:Complement C3c; D002784:Cholesterol