NOD1 and NOD2 Mediate Sensing of Periodontal Pathogens

Abstract

In bacterial infection, Nucleotide-binding Oligomerization Domain (NOD) 1 and NOD2 induce innate immune responses by recognizing fragments of the bacterial component peptidoglycan (PGN). To determine the roles of these receptors in detection of periodontal pathogens, we stimulated human embryonic kidney cells expressing NOD1 or NOD2 with heat-killed Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum or their soluble PGNs (sPGNs). All bacteria and their sPGNs could stimulate activation of NF-kappaB. However, there were differences in NOD1- and NOD2-stimulatory activities among the species of bacteria. P. gingivalis showed weaker NOD1- and NOD2-stimulatory activities than did other bacteria. These differences in activities were confirmed by production of interleukin-8 from oral epithelial cells stimulated with sPGNs. These findings indicate that both NOD1 and NOD2 might be involved in the recognition of periodontal pathogens, and that the weak NOD-stimulatory property of P. gingivalis might be helpful for survival in the periodontal pocket.

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

“…Upon incubation of the HEK293T cells with A. actinomycetemcomitans OMVs, we observed a strong activation of the cytoplasmic PRRs NOD1 and NOD2, supporting the presence of NOD1-and NOD2-active peptidoglycan in the vesicles. This is consistent with earlier in vitro studies using the HEK293T cell reporter assay, revealing that soluble A. actinomycetemcomitans PGN and heat-killed cells of this species act as potent inducers of both NOD1 and NOD2 (42). Conversely, another recent report using the same cell-based reporter assay suggested that the tested A. actinomycetemcomitans strain mainly triggered NOD1 (44).…”

“…It is conceivable that such a functional role of vesicles may be evident mainly in oral species possessing peptidoglycan with high NOD1-stimulatory activity, such as A. actinomycetemcomitans and the closely related mouse commensal NI1060. In contrast to these Pasteurellaceae species, Bacteroidetes organisms, including P. gingivalis, possess peptidoglycan exhibiting low levels of NOD1-stimulatory activity (42,43).…”

“…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). On the other hand, NOD-mediated innate immune responses targeting oral bacteria can also induce alveolar bone resorption (43).…”

NADPH oxidases: an overview from structure to innate immunity-associated pathologies

“…NOD1 recognizes peptidoglycan, a component of the bacterial cell wall, whereas NOD2 recognizes muramyl dipeptide, a peptidoglycan constituent of both Gram-positive and Gram-negative bacteria (Figure 2). 133 A different set of NLRs, including Ipaf and Naip, are activated through bacterial flagellin. NLRP3 (cryopyrin) is activated through a variety of molecules, including bacterial RNA, pore-forming toxins and endogenous ligands, including uric acid crystals and ATP.…”

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

“…Others studies have shown that supragingival and subgingival biofilms differently regulate the gene expressions of NLRP3 and AIM2 inflammasomes in human gingival fibroblasts (Bostanci et al, 2011), and the downregulation of NLRP3 and IL-1β expression is partly induced by P. gingivalis present in subgingival biofilms (Belibasakis et al, 2013). Although NOD1 and NOD2 are involved in the recognition of periodontal pathogens and in the immune responses modulation (Okugawa, 2010), the effect of its activation in osteoclast is still unknown. To investigate the role of the NOD2 receptor in osteoclastogenesis and bone resorption, we used an experimental periodontitis model with NOD2-deficient mice.…”