Induction of Bone Loss by Pathobiont-Mediated Nod1 Signaling in the Oral Cavity

Abstract

Summary Periodontitis is a common disease that is characterized by resorption of the alveolar bone and mediated by commensal bacteria that trigger host immune responses and bone destruction through unidentified mechanisms. We report that Nod1, an innate intracellular host receptor for bacterial peptidoglycan-related molecules, is critical for commensal-induced periodontitis in a mouse model. Mice lacking Nod1 exhibit reduced bone resorption as well as impaired recruitment of neutrophils to gingival tissues and osteoclasts to the alveolar bone, which mediate tissue and bone destruction. Further analysis showed that accumulation of a Nod1-stimulating commensal bacterium, NI1060, at gingival sites was sufficient to induce neutrophil recruitment and bone resorption. Genomic sequencing revealed that NI1060 is a mouse-specific bacterium that is related to bacteria associated with the development of aggressive periodontitis in humans. These findings provide insight into commensal-host interactions contributing to periodontitis and identify a potential target for preventing this common oral disease.

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

“…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). The reason(s) for this discrepancy is not known; however, A. actinomycetemcomitans straindependent differences cannot be excluded, as the latter study, in contrast to the others, used strain JP2, which produces high levels of leukotoxin (47).…”

“…This was demonstrated in a recent study in which NOD1 was found to be essential for bone loss in a mouse ligatureinduced periodontitis model (44). Interestingly, this observation was linked to the identification of an A. actinomycetemcomitanslike (Ͼ60% coding sequence identity) mouse commensal (termed NI1060) which accumulated at the site of ligature placement and acted as a significant NOD1 activator (44). Based on these observations, it was proposed that NI10160, and possibly the human pathogen A. actinomycetemcomitans, can trigger bone loss via stimulation of NOD1 (44).…”

“…These data suggest that NOD1-dependent sensing of OMV-derived PAMPs may have a physiological relevance in immunocompetent, i.e., myeloid cells. Thus, on the basis of the recent report by Jiao et al (44) indicating that A. actinomycetemcomitans triggers bone resorption mainly via NOD1, intracellular delivery of PGN via vesicles could act as a direct inducer of periodontal bone loss. 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.…”

“…On the other hand, NOD-mediated innate immune responses targeting oral bacteria can also induce alveolar bone resorption (43). This was demonstrated in a recent study in which NOD1 was found to be essential for bone loss in a mouse ligatureinduced periodontitis model (44). Interestingly, this observation was linked to the identification of an A. actinomycetemcomitanslike (Ͼ60% coding sequence identity) mouse commensal (termed NI1060) which accumulated at the site of ligature placement and acted as a significant NOD1 activator (44).…”

Macrophage Depletion Abates Porphyromonas gingivalis–Induced Alveolar Bone Resorption in Mice

“…The level of P. gingivalis infection in the mice treated with clodronate liposomes was decreased to 7-12%, and these animals exhibited the lowest amount of alveolar bone resorption. Hence, these results help to explain the important nexus between pathogen and inflammation, because they suggest that inflammation is an important component of the host-biofilm interaction for the emergence of the pathobiont that dysregulates the host response to produce dysbiosis and alveolar bone resorption (8,9,106). The predominance of the M1 macrophage phenotype in gingival tissue after P. gingivalis infection in the current study suggests that P. gingivalis may promote a dysregulated inflammatory response orchestrated by M1 macrophages.…”