title: Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice.
abstract: Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF-κB-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis.
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden; Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Johansson
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Zhang
authors.forename: Kristina
authors.initials: K
authors.lastname: Edfeldt
authors.forename: Anna M
authors.initials: AM
authors.lastname: Lundberg
authors.forename: Malin C
authors.initials: MC
authors.lastname: Levin
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yuan
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Hann
authors.initials: H
authors.lastname: Low
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rios
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Zhong-Qun
authors.initials: ZQ
authors.lastname: Yan
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D006801:Humans; D006937:Hypercholesterolemia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate / Q000276:immunology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology* / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012333:RNA, Messenger
keywords: Atherosclerosis; Inflammation; Innate immunity; Nucleotide-binding oligomerization domain-containing protein 2; Pattern recognition receptor