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Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice.
- Source :
-
European journal of immunology [Eur J Immunol] 2014 Oct; Vol. 44 (10), pp. 3081-92. Date of Electronic Publication: 2014 Aug 25. - Publication Year :
- 2014
-
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.<br /> (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Atherosclerosis metabolism
Blotting, Western
Disease Models, Animal
Humans
Hypercholesterolemia immunology
Hypercholesterolemia metabolism
Hypercholesterolemia pathology
Immunohistochemistry
In Situ Nick-End Labeling
Inflammation metabolism
Inflammation pathology
Mice
Mice, Knockout
Necrosis
Nod2 Signaling Adaptor Protein metabolism
Plaque, Atherosclerotic metabolism
Plaque, Atherosclerotic pathology
RNA, Messenger analysis
Real-Time Polymerase Chain Reaction
Atherosclerosis immunology
Atherosclerosis pathology
Immunity, Innate immunology
Inflammation immunology
Nod2 Signaling Adaptor Protein immunology
Plaque, Atherosclerotic immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4141
- Volume :
- 44
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 25042478
- Full Text :
- https://doi.org/10.1002/eji.201444755