Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice

Eur J Immunol. 2014 Oct;44(10):3081-92. doi: 10.1002/eji.201444755. Epub 2014 Aug 25.


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.

Keywords: Atherosclerosis; Inflammation; Innate immunity; Nucleotide-binding oligomerization domain-containing protein 2; Pattern recognition receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / immunology*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Blotting, Western
  • Disease Models, Animal
  • Humans
  • Hypercholesterolemia / immunology
  • Hypercholesterolemia / metabolism
  • Hypercholesterolemia / pathology
  • Immunity, Innate* / immunology
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Mice, Knockout
  • Necrosis
  • Nod2 Signaling Adaptor Protein / immunology*
  • Nod2 Signaling Adaptor Protein / metabolism
  • Plaque, Atherosclerotic / immunology*
  • Plaque, Atherosclerotic / metabolism
  • Plaque, Atherosclerotic / pathology
  • RNA, Messenger / analysis
  • Real-Time Polymerase Chain Reaction


  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • RNA, Messenger