title: NOD2-mediated innate immune signaling regulates the eicosanoids in atherosclerosis.
abstract: OBJECTIVE
  The activity of eicosanoid pathways is critical to the inflammatory and immune responses that are associated with the progression of atherosclerosis. Yet, the signals that regulate these pathways are poorly understood. Here, we address whether the innate immune signals of nucleotide-binding oligomerization domain-containing protein (NOD) 2 affect eicosanoids metabolism in atherosclerosis.
  
  
  RESULTS
  Analysis of human carotid plaques revealed that NOD2 was abundantly expressed at both mRNA and protein levels by endothelial cells and macrophages. Stimulation of NOD2 in ex vivo-cultured carotid plaques by muramyl dipeptide, an extrinsic ligand of NOD2, led to release of prostaglandin E2, upregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, and to downregulation of cyclooxygenase-1. NOD2 was coexpressed with cyclooxygenase-2 in lesional macrophages. NOD2-induced cyclooxygenase-2 expression in macrophages was dependent on p38 mitogen-activated protein kinase activation and was mediated by interleukin-1β and tumor necrosis factor-α. Selective lipidomic analysis of the eicosanoids released by the carotid plaques characterized the metabolites of 12-, 5-, and 15-lipoxygenase as the predominant eicosanoids that were produced by the atherosclerotic lesion in the absence of additional stimuli. Unlike the prostaglandin E2 pathway, metabolic activity of the lipoxygenase pathways was not altered on the short-term activation of NOD2 in carotid plaques.
  
  
  CONCLUSIONS
  These results suggest that atherosclerosis may involve enhanced NOD2-mediated innate immunity. Activation of NOD2 preferentially upregulates the prostaglandin E2 pathway. Nevertheless, lipoxygenase pathways, such as 12-lipoxygenase, predominate the basal synthesis and metabolism of eicosanoids in atherosclerotic plaques. These findings provide new insights into the regulation of eicosanoids in atherosclerosis.
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hui-Qing
authors.initials: HQ
authors.lastname: Liu
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Zhang
authors.forename: Kristina
authors.initials: K
authors.lastname: Edfeldt
authors.forename: Manon Oude
authors.initials: MO
authors.lastname: Nijhuis
authors.forename: Helena
authors.initials: H
authors.lastname: Idborg
authors.forename: Magnus
authors.initials: M
authors.lastname: Bäck
authors.forename: Joy
authors.initials: J
authors.lastname: Roy
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Dominique P
authors.initials: DP
authors.lastname: de Kleijn
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Zhong-Qun
authors.initials: ZQ
authors.lastname: Yan
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000378:metabolism; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000378:metabolism; D008024:Ligands; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015777:Eicosanoids; D053583:Interleukin-1beta; D008024:Ligands; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C583212:ALOX5 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone
keywords: atherosclerosis; eicosanoids; immunity, innate; inflammation; pattern recognition receptors; peptidoglycan