Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 44, Issue 10, Pages 3081-3092Publisher
WILEY
DOI: 10.1002/eji.201444755
Keywords
Atherosclerosis; Inflammation; Innate immunity; Nucleotide-binding oligomerization domain-containing protein 2; Pattern recognition receptor
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Funding
- Swedish Research Council
- Swedish Heart-Lung Foundation
- European Union projects (Immunath, AtheroRemo, AtheroFlux)
- O. E. och Edla Johanssons vetenskapliga stiftelse
- KI foundation
- KI Joint funding postdoc position
- Swedish Society for Medical Research
- Chinese Scholarship Council
- Peking University Health Science Center
- National Health and Medical Research Council of Australia
- Novo Nordisk Fonden [NNF13OC0004973] Funding Source: researchfish
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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-kappa B-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.
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