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Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice
Karolinska Institute, Sweden; University of Gothenburg, Sweden.
Karolinska Institute, Sweden; Peking University, Peoples R China.
Karolinska Institute, Sweden; Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
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2014 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 44, no 10, 3081-3092 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-VCH Verlag , 2014. Vol. 44, no 10, 3081-3092 p.
Keyword [en]
Atherosclerosis; Inflammation; Innate immunity; Nucleotide-binding oligomerization domain-containing protein 2; Pattern recognition receptor
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-112483DOI: 10.1002/eji.201444755ISI: 000343827600024PubMedID: 25042478OAI: oai:DiVA.org:liu-112483DiVA: diva2:766738
Note

Funding Agencies|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

Available from: 2014-11-28 Created: 2014-11-28 Last updated: 2017-12-05

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Li, WeiYuan, Ximing

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