Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice |
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| Authors: | 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 |
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| Affiliation: | 1. Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden;2. Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;3. Health Science Center, Peking University, Beijing, China;4. Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden;5. Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;6. Department of Clinical and Experimental Medicine, Link?ping University, Link?ping, Sweden;7. Department of Molecular Genetics, Novo Nordisk, Copenhagen, Denmark;8. Laboratory of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;9. British Heart Foundation, Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom |
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| 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. |
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| Keywords: | Atherosclerosis Inflammation Innate immunity Nucleotide‐binding oligomerization domain‐containing protein 2 Pattern recognition receptor |
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