Oral infection of mice with Fusobacterium nucleatum results in macrophage recruitment to the dental pulp and bone resorption

Abstract

BackgroundFusobacterium nucleatum is a Gram-negative anaerobic bacterium associated with periodontal disease. Some oral bacteria, like Porphyromonas gingivalis, evade the host immune response by inhibiting inflammation. On the other hand, F. nucleatum triggers inflammasome activation and release of danger-associated molecular patterns (DAMPs) in infected gingival epithelial cells.MethodsIn this study, we characterized the pro-inflammatory response to F. nucleatum oral infection in BALB/c mice. Western blots and ELISA were used to measure cytokine and DAMP (HMGB1) levels in the oral cavity after infection. Histology and flow cytometry were used to observe recruitment of immune cells to infected tissue and pathology.ResultsOur results show increased expression and production of pro-inflammatory cytokines during infection. Furthermore, we observe that F. nucleatum infection leads to recruitment of macrophages in different tissues of the oral cavity. Infection also contributes to osteoclast recruitment, which could be involved in the observed bone resorption.ConclusionsOverall, our findings suggest that F. nucleatum infection rapidly induces inflammation, release of DAMPs, and macrophage infiltration in gingival tissues and suggest that osteoclasts may drive bone resorption at early stages of the inflammatory process.

Immunological Pathways Triggered byPorphyromonas gingivalisandFusobacterium nucleatum: Therapeutic Possibilities?

“…These results show that inflammasome activation after F. nucleatum infection is a robust but complex regulated process. In oral infection in mice, we showed that F. nucleatum induced the expression and secretion of several proinflammatory cytokines, including the inflammasome-dependent IL-1 β [130]. In agreement with in vitro and mouse model studies, the expression of the components of the NLRP3 inflammasome was also shown to be increased in periapical lesions in human subjects with periapical periodontitis [131].…”

Persistent Exposure to Fusobacterium nucleatum Triggers Chemokine/Cytokine Release and Inhibits the Proliferation and Osteogenic Differentiation Capabilities of Human Gingiva-Derived Mesenchymal Stem Cells

“…Uitto et al reported that F. nucleatum increase infected epithelial cell migration and survival by increasing collagenase 3 production (Uitto et al, 2005). F. nucleatum infection leads to the recruitment of macrophages and osteoclasts, finally resulting in gingival inflammation and bone resorption (Johnson et al, 2018). In human GECs, F. nucleatum upregulates the gene expression levels of IL-1, IL-6, IL-8, SOD2, CCL20, CXCL1, CXCL3, and CSF2 partly by activating the NF-κB, mitogen-activated protein kinase (MAPK) p38, and MAPK kinase/extracellular signal-regulated kinase (MEK/ERK) pathways (Huang et al, 2004;Milward et al, 2007;Ramage et al, 2017).…”

Danger signals in oral cavity-related diseases

“…Whether such signaling is required in vivo for periodontal disease development is currently unclear, however P. gingivalis can secrete a nucleoside diphosphate kinase‐like enzyme that can remove ATP and inhibit such signaling . In addition, recent studies have begun to indicate a role for the DAMPs serum amyloid A and HMGB1 in periodontal disease, as these are increased in tissue and GCF and can activate TLR signaling in mouse models of periodontal disease . Systemic administration of anti‐HMGB1 inhibited periodontal inflammation and bone loss in a bacterial induced murine model, highlighting a potential role in periodontal progression …”