title: IL-19 Halts Progression of Atherosclerotic Plaque, Polarizes, and Increases Cholesterol Uptake and Efflux in Macrophages.
abstract: Atherosclerosis regression is an important clinical goal, and treatments that can reverse atherosclerotic plaque formation are actively being sought. Our aim was to determine whether administration of exogenous IL-19, a Th2 cytokine, could attenuate progression of preformed atherosclerotic plaque and to identify molecular mechanisms. LDLR(-/-) mice were fed a Western diet for 12 weeks, then administered rIL-19 or phosphate-buffered saline concomitant with Western diet for an additional 8 weeks. Analysis of atherosclerosis burden showed that IL-19-treated mice were similar to baseline, in contrast to control mice which showed a 54% increase in plaque, suggesting that IL-19 halted the progression of atherosclerosis. Plaque characterization showed that IL-19-treated mice had key features of atherosclerosis regression, including a reduction in macrophage content and an enrichment in markers of M2 macrophages. Mechanistic studies revealed that IL-19 promotes the activation of key pathways leading to M2 macrophage polarization, including STAT3, STAT6, Kruppel-like factor 4, and peroxisome proliferator-activated receptor γ, and can reduce cytokine-induced inflammation in vivo. We identified a novel role for IL-19 in regulating macrophage lipid metabolism through peroxisome proliferator-activated receptor γ-dependent regulation of scavenger receptor-mediated cholesterol uptake and ABCA1-mediated cholesterol efflux. These data show that IL-19 can halt progression of preformed atherosclerotic plaques by regulating both macrophage inflammation and cholesterol homeostasis and implicate IL-19 as a link between inflammation and macrophage cholesterol metabolism.
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gabunia
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ellison
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Sheri
authors.initials: S
authors.lastname: Kelemen
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Farah
authors.initials: F
authors.lastname: Kako
authors.affiliation: Center for Inflammation, Translational, and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: William D
authors.initials: WD
authors.lastname: Cornwell
authors.affiliation: Center for Inflammation, Translational, and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
authors.affiliation: Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Datta
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York.
authors.forename: Mireille
authors.initials: M
authors.lastname: Ouimet
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania. Electronic address: mautieri@temple.edu.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Autieri
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D015415:Biomarkers / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D066273:Diet, Western; D018450:Disease Progression; D005260:Female; D007249:Inflammation; D016753:Interleukin-10 / Q000494:pharmacology*; D007378:Interleukins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000188:drug therapy*; D050791:STAT Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D015415:Biomarkers; C498891:Il19 protein, mouse; D007378:Interleukins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma; D050791:STAT Transcription Factors; D016753:Interleukin-10; D002784:Cholesterol