title: Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming.
abstract: Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.
authors.affiliation: Medizinische Klinik und Poliklinik II, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zimmer
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Grebe
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany. German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway.
authors.forename: Siril S
authors.initials: SS
authors.lastname: Bakke
authors.affiliation: Medizinische Klinik und Poliklinik II, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Bode
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway.
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.affiliation: Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulas
authors.affiliation: Department of Neurology, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway.
authors.forename: Mona
authors.initials: M
authors.lastname: Skjelland
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Dominic
authors.initials: D
authors.lastname: De Nardo
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany.
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Labzin
authors.affiliation: Institute of Clinical Chemistry und Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kerksiek
authors.affiliation: Addi and Cassi Fund, Reno, NV 89511, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Hempel
authors.affiliation: Clinic and Polyclinic for Neurology, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: Lipid Metabolism Unit, Center for Computational and Integrative Biology, Boston, MA 02114, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hawxhurst
authors.affiliation: Lipid Metabolism Unit, Center for Computational and Integrative Biology, Boston, MA 02114, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.affiliation: Medizinische Klinik und Poliklinik I, University Hospital Bonn, 53105 Bonn, Germany. Faculty of Health Sciences, University of Southern Denmark Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.affiliation: Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, 141 86 Huddinge, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77004, USA.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.affiliation: CSL Behring, King of Prussia, PA 19406, USA.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.affiliation: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.affiliation: German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Medizinische Klinik und Poliklinik II, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Institute of Clinical Chemistry und Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany. German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. eicke.latz@uni-bonn.de.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D003460:Crystallization; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000071518:Liver X Receptors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D047392:beta-Cyclodextrins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000071518:Liver X Receptors; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol