Autor: |
Maria E, Johansson, Xiao-Ying, Zhang, Kristina, Edfeldt, Anna M, Lundberg, Malin C, Levin, Jan, Borén, Wei, Li, Xi-Ming, Yuan, Lasse, Folkersen, Per, Eriksson, Ulf, Hedin, Hann, Low, Dmitri, Sviridov, Francisco J, Rios, Göran K, Hansson, Zhong-Qun, Yan |
Rok vydání: |
2014 |
Předmět: |
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Zdroj: |
European journal of immunology. 44(10) |
ISSN: |
1521-4141 |
Popis: |
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. |
Databáze: |
OpenAIRE |
Externí odkaz: |
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