Emerging roles of immunostimulatory oral bacteria in periodontitis development

Abstract

Periodontitis is a common dental disease which results in irreversible alveolar bone loss around teeth, and subsequent tooth loss. Previous studies have focused on bacteria that damage the host and the roles of commensals to facilitate their colonization. Although some immune responses targeting oral bacteria protect the host from alveolar bone loss, recent studies show that particular host defense responses to oral bacteria can induce alveolar bone loss. Host-damaging and immunostimulatory oral bacteria cooperatively induce bone loss by inducing gingival damage followed by immunostimulation. In mouse models of experimental periodontitis induced by either Porphyromonas gingivalis or ligature, γ-proteobacteria accumulate and stimulate host immune responses to induce host damage. Here we review the differential roles of individual bacterial groups in promoting bone loss through the induction of host damage and immunostimulation.

Keywords: NOD1; alveolar bone absorption; innate immunity; neutrophil recruitment; pathobiont; periodontitis.

Figure 1. Models for host protective and damaging immune responses to oral bacteria in periodontitis

Alveolar bone loss in periodontitis is primarily associated with immune responses to oral bacteria. The immune responses provide protection against translocated bacteria (T) but also mediate alveolar bone resorption which is harmful to host tissues. Host protective immune responses include elimination of pathogens by phagocytic cells (P) and production of antigen-specific immunoglobulin (IGs) which are mediated by antigen presenting phagocytic cells and activated T cells (actT). Inducible NO synthase (iNOS) is also known to be involved in host protective immune responses. The number of bone absorbing osteoclasts increase at sites below the damaged gingiva during periodontitis development. In the model, host damaging red complex bacteria (R) damage the epithelial barrier function. The epithelial damage allows the translocation of harmful bacteria or immunostimulatory bacterial components into the gingival tissue. NOD1 ligands are released from particular types of oral bacteria (N) which induces recruitment of phagocytotic cells to the damaged gingiva via induction of chemokines such as CXCLs and CCLs (e.g. IL-8 and CCL3, respectively). Translocated bacteria (T) are eliminated by phagocytosis and other mechanisms through recruited immune cells, bacterial opsonization, and complement activation. A red complex bacterium such as P. gingivalis possesses the ability to process complement factors. The processed complement factors further induce recruitment of myelomonocytic cells to the lesion. IL-17 inhibits expression of Del-1 that interferes with neutrophil adhesion and molecule-dependent neutrophil recruitment. Some myelomonocytic cells are major sources of immunostimulatory molecules which facilitate the development of secondary immune responses to the bacteria. Immunization against P. gingivalis is shown to protect hosts from alveolar bone loss. Myelomonocytic cells also release bone loss-inducing inflammatory cytokines, TNF and IL-1, upon bacterial stimulation of PRRs such as TLR2. RANKL is expressed on activated T, B cells and osteoblasts that are stimulated by these inflammatory cytokines, T cells, and is important for alveolar bone loss in experimental periodontitis models. Therefore, protective immune responses that are activated to eliminate translocated bacteria can also damage the host by the induction of alveolar bone loss.

Figure 2. Distinct roles of host damaging and immunostimulatory bacteria in the development of periodonditis

As shown in Figure 1, host immune responses to oral bacteria are critical for periodontitis development. A particular group of periodontitis-associated keystone pathogens possess the ability to subvert and escape recognition by the host immune system via several mechanisms including intracellular invasion and blockage of host immune signaling [70]. The latter events are likely important for keystone pathogens to establish a dysbiotic bacterial community by avoiding their elimination in the oral cavity. In addition, another type of commensal bacteria is recognized by the host innate immune system to elicit inflammatory responses that result in bone loss. NOD1 ligands are immunostimulatory molecules that are released from bacteria and therefore they can stimulate immune responses remotely from the bacteria. Thus, a model is proposed by which two distinct bacterial groups, namely host damaging (keystone pathogens) and immunostimulatory such as NOD1-stimulatory bacteria act synergistically to induce periodontitis. In the model, keystone pathogens possess the ability to induce damage to the epithelial barrier via virulence factors such as proteases (red complex bacteria) and/or toxins (A. actinomycetemcomitans) which enable immunostimulatory bacterial molecules such as NOD1 ligands and/or bacteria to translocate deeper into the tissue and to elicit inflammatory responses and bone loss.