NOD2-Mediated Innate Immune Signaling Regulates the Eicosanoids in Atherosclerosis

Liu, Huiqing; Zhang, Xiaoying; Edfeldt, Kristina; Nijhuis, Manon Oude; Idborg, Helena; Bäck, Magnus; Roy, Joy; Hedin, Ulf; Jakobsson, Per‐Johan; Laman, Jon D.; Kleijn, Dominique Pv de; Pasterkamp, Gérard; Hansson, Göran K.; Yan, Zhenghua

doi:10.1161/atvbaha.113.301715

Cited by 40 publications

(40 citation statements)

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“…Consistent with a role for NOD2 ligation in activation of MAPK p38 in monocytes [20], we found that stimulation of NOD2 in human atherosclerotic lesions especially enhanced the activation of p38 and NF-κB ( Fig. 5A and B), and led to robust production of IL-6, IL-8, IL-10, and IL-1β (Fig.…”

Section: Nod2 Cognate Ligand Instigates Innate Immune Signaling Pathwsupporting

confidence: 84%

“…This is characterized by expression of high levels of proinflammatory cytokines, high production of prostaglandin E2, and promotion of Th1-type responses [20]. Additionally, endothelial cells lining human atherosclerotic lesions also express high levels of NOD2 [20], designating arterial endothelial cells as the second largest population of NOD2-competent cells in atherosclerosis after macrophages. The present studies suggest that upregulation of endothelial NOD2 sensitizes endothelial cells to NOD2 stimuli in atherosclerosis, linking NOD2 stimulation to progressive recruitment of monocytes and T lymphocytes into atherosclerotic lesion.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Kwon et al reported that lack of NOD2 signaling increases neointimal formation in mice after vascular injury [19]. We recently showed that stimulation of NOD2 in human carotid plaque results in rapid activation of the prostaglandin E2 pathway and IL-1β signaling, the first evidence supporting the involvement of NOD2 in human atherosclerosis [20]. Besides the traditional risk factors such as hypercholesterolemia, hypertension, obesity, and smoking, chronic infection with Porphyromonas gingivalis has been shown to promote atherosclerosis.…”

Section: Introductionmentioning

confidence: 91%

“…Our recent study shows that lesional macrophages carry the predominant NOD2 innate immunity, and respond to environmental cues such as microbial peptidoglycan with acquisition of classic M1 activation. This is characterized by expression of high levels of proinflammatory cytokines, high production of prostaglandin E2, and promotion of Th1-type responses [20]. Additionally, endothelial cells lining human atherosclerotic lesions also express high levels of NOD2 [20], designating arterial endothelial cells as the second largest population of NOD2-competent cells in atherosclerosis after macrophages.…”

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confidence: 99%

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Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice

et al. 2014

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Genetic studies have demonstrated that loss-of-function mutations in NOD2 are associated with several chronic inflammatory disorders, including Crohn's disease [9,10], whereas gain-offunction mutations in NOD2 correlate with Blau syndrome [11], and early-onset sarcoidosis [12], underscoring a crucial role for NOD2 in immune homoeostasis. However, the data on such mutations in cardiovascular disease are inconclusive [13][14][15].The involvement of NOD2 in inflammatory cardiovascular diseases was initially postulated based on the observations that vascular endothelial cells express low basal levels of NOD2 [16,17] and that depletion of RIP2 in myeloid cells regulates the development of atherosclerosis by induction of TLR4-mediated macropinocytosis of LDL in macrophages [18]. Moreover, Kwon et al. reported that lack of NOD2 signaling increases neointimal formation in mice after vascular injury [19]. We recently showed that stimulation of NOD2 in human carotid plaque results in rapid activation of the prostaglandin E2 pathway and IL-1β signaling, the first evidence supporting the involvement of NOD2 in human atherosclerosis [20]. Besides the traditional risk factors such as hypercholesterolemia, hypertension, obesity, and smoking, chronic infection with Porphyromonas gingivalis has been shown to promote atherosclerosis. In this regard, innate immune surveillance mechanism may provide essential protection against atherosclerosis. A recent study on ApoE −/− mice has revealed an indispensable role for NOD2 in protecting the mice from oral infection by Porphyromonas gingivalis, thereby restraining infection-mediated oral bone resorption, aortic inflammation, and plaque development [21]. Together, these findings indicate that NOD2 is involved in multiple aspects of cardiovascular diseases. However, whether NOD2 plays a direct role in atherosclerotic plaque development is not yet proven. This study was designed to elucidate the function of NOD2 signaling in atherosclerosis. By studying MDP-induced NOD2 signaling in atherosclerosis-prone mice and NOD2-deficient chimeric mice, we show that NOD2 promotes vascular inflammation and contributes to the expansion of the lipid-rich necrotic core in hyperlipidemic mice. Deploying an ex vivo culture system of human atherosclerotic plaque, we also characterized NOD2 signaling mechanisms in human atherosclerosis. Fig. 1). Results ActivationDespite no significant alteration in body weight and plasma cholesterol levels (Table 1), MDP-treated mice exhibited a dramatic increase in atherosclerosis in the aortic root compared with the controls (Fig. 1A and B). In association with the greater lesion burden, MDP-treated mice experienced enhanced vascular inflammation, as evidenced by significant upregulation of VCAM-1 and IL-6, and a tendency of elevation in TNF-α, MCP-1, IFN-γ, and IL-10 (Fig. 1C). Further, MDP increased the infiltration of CD68-positive macrophages and levels of COX2, implying macrophage activation in the lesion ( Fig. 1C-E). In parallel, the MDP treatment also resulted in...

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Section: Nod2 Cognate Ligand Instigates Innate Immune Signaling Pathwsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

mentioning

confidence: 99%

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Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice

et al. 2014

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“…22 Despite the considerable evidence for innate defense responses by VSMCs in vitro, analyses of clinical specimens of vascular inflammation demonstrate minimal TLR and NOD2 expression by VSMCs in situ as compared with endothelial cells, macrophages, and dendritic cells. [27][28][29][30] An exception is the in vivo demonstration of robust responses to ds-RNA by TLR3/MDA5/RIG-I expressing human coronary artery segments interposed into the aorta of immunodeficient mouse hosts in which resident leukocytes are absent after early emigration from the graft. 22 Remarkably, this study also showed greater responses of isolated VSMCs to ds-RNA than 10-fold larger numbers (but equivalent total surface areas) of peripheral blood mononuclear cells; similar observations of more substantial TLR3-induced signaling are seen in other human primary cell types, such as endothelial cells and fibroblasts compared with macrophages and dendritic cells.…”

Section: Initiation and Amplification Of Innate Immune Responses By Vmentioning

confidence: 99%

Inflammatory and Immune Responses in the Arterial Media

Tellides

Pober

2015

Circulation Research

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Inflammatory arterial diseases differentially affect the compartments of the vessel wall. The intima and adventitia are commonly involved by the disease process, with luminal and microvascular endothelial cells playing a critical role in the recruitment and activation of leukocytes. In contrast, the avascular media is often spared by immune-mediated disorders. Surprisingly, vascular smooth muscle cells (VSMCs), the predominant and often exclusive cell type of the media, are capable of robust proinflammatory responses to diverse stressors. The multiple cytokines and chemokines produced within the media can profoundly affect macrophage and T cell function, thus amplifying and shaping innate and adaptive immune responses. On the other hand, VSMCs and the extracellular matrix that they produce also display significant anti-inflammatory properties. The balance between the pro- and anti-inflammatory effects of VSMCs and their extracellular matrix versus the strength of the inciting immunologic events determines the pattern of medial pathology. Limitations on the extent of medial infiltration and injury, defined as medial immunoprivilege, are typically seen in arteriosclerotic diseases, such as atherosclerosis and transplant vasculopathy. Conversely, breakdown of medial immunoprivilege that manifests as more intense leukocytic infiltrates, loss of VSMCs, and destruction of the extracellular matrix architecture is a general feature of certain aneurysmal diseases and vasculitides. In this review, we consider the inflammatory and immune functions of VSMCs and how they may lead to medial immunoprivilege or medial inflammation in arterial diseases.

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TNF‐α‐Induced NOD2 and RIP2 Contribute to the Up‐Regulation of Cytokines Induced by MDP in Monocytic THP‐1 Cells

Chen

Xiao

Xie

et al. 2018

J of Cellular Biochemistry

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Nucleotide-binding oligomerization domain containing 2 (NOD2)-induced signal transduction and cytokine production is regulated by a number of factors. However, the feedback effect of the pro-inflammatory TNF-α on NOD2-induced inflammation is not fully understood. In this study, we found unexpectedly that TNF-α up-regulated NOD2 ligand MDP-induced production of the CXC chemokines, including CXCL1, 2, and 8, and the pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in a dose-dependent manner at both mRNA and protein levels in monocytic THP-1 cells. Though TNF-α induced the up-regulation of ubiquitin-editing enzyme A20, an important negative regulator for Toll-like receptor- and NOD2-induced inflammatory responses, the over-expression of A20 by gene transfer did not reversed MDP-induced production of cytokines, suggested that A20 did not regulate the functions of NOD2 in THP-1 cells. Meanwhile, we found that TNF-α up-regulated NOD2 and its down-stream adaptor protein RIP2 at both mRNA and protein levels. MDP induced the activation of ERK, JNK, p38 and NF-κB, and TNF-α pre-treatment augmented this activation. The results from pharmacological inhibition assay showed that cytokine production was dependent on MAPK signaling. In addition, we found that the pre-treatment of THP-1 cells with MDP down-regulated the mRNA levels of cytokine induced by MDP re-treatment. MDP pre-treatment up-regulated NOD2, but down-regulated RIP2, and down-regulated NOD2 signal transduction induced by MDP re-stimulation. Taking together, these results suggested that TNF-α is a positive regulator for NOD2 functions via up-regulation of NOD2 and its signal adaptor RIP2, and TNF-α-induced A20 does not regulate MDP-induced inflammatory responses in THP-1 cells. J. Cell. Biochem. 119: 5072-5081, 2018. © 2017 Wiley Periodicals, Inc.

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NOD2-Mediated Innate Immune Signaling Regulates the Eicosanoids in Atherosclerosis

Cited by 40 publications

References 47 publications

Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice

Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice

Inflammatory and Immune Responses in the Arterial Media

TNF‐α‐Induced NOD2 and RIP2 Contribute to the Up‐Regulation of Cytokines Induced by MDP in Monocytic THP‐1 Cells

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