Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

Abstract

Significance Apolipoprotein E −/− (ApoE −/− ) mice deficient in nucleotide binding oligomerization domain-containing protein 2 (NOD2) and subjected to an oral gavage of Porphyromonas gingivalis developed elevated serum inflammatory cytokines, cholesterol, alveolar bone loss, and atherosclerosis. Stimulation of NOD2 by Muramyl DiPeptide (MDP) in ApoE −/− mice reduced P. gingivalis -induced inflammatory cytokines, cholesterol, alveolar bone loss, and atherosclerosis by reducing the expression of inhibitor of NF-κB kinase-β, NF-κB, JNK mRNA, and TNF-α protein levels. A reduction in body weight gain was observed in ApoE −/− mice fed a high-fat diet (HFD) and injected with MDP compared to ApoE −/− mice fed a HFD but saline injected. MDP activation of NOD2 should be considered in the treatment of inflammatory processes affecting atherosclerosis, bone loss, and possibly, weight gain.

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

“…During preparation of this manuscript, we noticed that Yuan et al recently published an interesting study on the role of NOD2-dependent innate immunity in atherosclerosis [21]. Their study demonstrates that NOD2 signaling is an indispensable host defense mechanism protecting hyperlipidemic mice from P. gingivalis infection, and the infection resulted proatherogenic effects.…”

“…Because of the epithelial NOD2 deficiency, the mice with a global NOD2 defect are susceptible to infection and manifest reduced bacterial clearance and increased intestine microbe translocation, leading to the development of chronic inflammation and the systemic immune responses seen in Crohn's disease [38,39]. These effects of epithelial NOD2 deficiency possibly account for the accelerated atherosclerosis seen in ApoE −/− NOD2 −/− mice compared with ApoE −/− mice [21].…”

“…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.…”

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

“…Uptake of LPS from gut microbiota has been demonstrated to result in increased internalization of LPS-rich lipoproteins into adipocytes and promote macrophage conversion from the M2 form to the inflammatory M1 form [79]. NOD2 is also included in the GO pathway for regulation of lipid metabolism (0045834) as it is a positive regulator of phosphatidylinositol 3-kinase activity and has been demonstrated to promote vascular inflammation and formation of lipid-rich atherosclerotic lesions in hypercholesterolemic LDLR −/− mice [80,81]. NOD2 interacts with another BMI-related differentially methylated inflammatory gene locus at SOCS3 (suppressor of cytokine signaling 3), a negative regulator of cytokine signaling.…”

Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation

“…NOD1 and NOD2 are functionally expressed in various cell types of oral tissues, e.g., epithelial cells, gingival fibroblasts, and periodontal ligament cells (38)(39)(40). In vivo evidence that stimulation of NOD2 reduced P. gingivalis-induced periodontal inflammation and alveolar bone loss supports a crucial role of NLRs in preventing periodontitis development (41). Hence, low NOD-stimulatory activity might be helpful for bacterial survival in the periodontal pocket (42).…”