title: Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo.
abstract: We have recently reported that monocytes can undergo functional and transcriptional reprogramming towards a long-term pro-inflammatory phenotype after brief in vitro exposure to atherogenic stimuli such as oxidized LDL. This process is termed 'trained immunity', and is mediated by epigenetic remodeling and a metabolic switch towards increased aerobic glycolysis. We hypothesize that trained immunity contributes to atherogenesis. Therefore, we investigated the inflammatory phenotype and epigenetic remodeling of monocytes from patients with and without established atherosclerosis.
  
  
  
  Monocytes were isolated from 20 patients with severe symptomatic coronary atherosclerosis (total plaque score >4 on coronary computed tomography angiography) and 17 patients with asymptomatic carotid atherosclerosis and matched controls for both groups. Ex vivo stimulation, RNA analysis and chromatin immunoprecipitation were performed.
  
  
  
  Monocytes from patients with symptomatic atherosclerosis have a higher production of pro-inflammatory cytokines upon LPS stimulation than healthy controls (TNFα 499 ± 102 vs. 267 ± 45 pg/ml, p = 0.01). This was associated with lower histone 3 lysine 4 trimethylation (H3K4me3) (19% vs. 33%, p = 0.002), and lower H3K27me3 (0.005% vs. 0.8%, p < 0.0001) on the TNFα promoter. Furthermore, relative mRNA expression of the glycolytic rate limiting enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 was higher in patients (0.7 ± 0.2 vs. 0.3 ± 0.1 resp. 1.7 ± 0.2 vs. 1.0 ± 0.1, p = 0.007 resp. 0.003) compared to control individuals. Interestingly, this pro-inflammatory phenotype was only present in patients with symptomatic atherosclerosis, and not in patients with asymptomatic carotid atherosclerosis.
  
  
  
  Circulating monocytes of patients with symptomatic, but not asymptomatic, atherosclerosis have a pro-inflammatory phenotype and increased expression of glycolytic enzymes, associated with epigenetic remodeling at the level of histone methylation.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Siroon
authors.initials: S
authors.lastname: Bekkering
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: van den Munckhof
authors.affiliation: Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Nielen
authors.affiliation: Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Evert
authors.initials: E
authors.lastname: Lamfers
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Dinarello
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Rutten
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Marc E R
authors.initials: ME
authors.lastname: Gomes
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Niels.Riksen@Radboudumc.nl.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
mesh_terms: D000368:Aged; D050197:Atherosclerosis / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D003324:Coronary Artery Disease / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006019:Glycolysis; D006657:Histones / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D008077:Lipoproteins, LDL / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000378:metabolism
chemical_list: D016207:Cytokines; D006657:Histones; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein
keywords: Atherosclerosis; Epigenetics; Inflammation; Metabolism; Monocytes