Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy

Abstract

Recent advances indicate that periodontitis is driven by reciprocally reinforced interactions between a dysbiotic microbiome and dysregulated inflammation. Inflammation is not only a consequence of dysbiosis but, via mediating tissue dysfunction and damage, fuels further growth of selectively dysbiotic communities of bacteria (inflammophiles), thereby generating a self-sustained feed-forward loop that perpetuates the disease. These considerations provide a strong rationale for developing adjunctive host-modulation therapies for the treatment of periodontitis. Such host-modulation approaches aim to inhibit harmful inflammation and promote its resolution or to interfere directly with downstream effectors of connective tissue and bone destruction. This paper reviews diverse strategies targeted to modulate the host periodontal response and discusses their mechanisms of action, perceived safety, and potential for clinical application.

Keywords: complement; cytokines; dysbiosis; host modulation; inflammation; inhibitors; periodontitis; resolution; therapeutics.

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

Figure 1.. Periodontal disease pathogenesis.

Periodontal health is maintained by homeostatic immunity and is associated with symbiotic microbiota. Periodontitis is associated with a dysbiotic polymicrobial community, in which different members have distinct and synergistic roles that promote destructive inflammation. Keystone pathogens — which are aided by accessory pathogens in terms of nutritional and/or colonization support — initially subvert host immunity leading to the emergence of dysbiotic microbiota, in which commensal-turned pathobionts overactivate the inflammatory response and cause tissue destruction. Inflammation in turn can exacerbate dysbiosis through provision of nutrients for the bacteria (derived from tissue breakdown products; e.g., collagen peptides and heme-containing compounds). Therefore, inflammation and dysbiosis are reciprocally reinforced and generate a positive-feedback loop. This self-sustaining loop may underlie the chronicity of periodontitis, the development of which requires a susceptible host. Risk factors include (but are not limited to) the presence of bacteria that subvert the host response, systemic disease, smoking, aging, high-fat diet, and immune deficiencies. These factors could promote dysbiosis by acting individually or more effectively in combination.

Figure 2.. Targets for host-modulation interventions in periodontitis.

Periodontitis arises from the disruption of host-microbe homeostasis in susceptible individuals leading to dysbiosis and destructive inflammation that not only activates osteoclastogenesis and bone loss but also provides nutrients (tissue breakdown products) that enable the dysbiotic microbiota to grow and persist. Shown are important therapeutic targets and potential interventions, most of which are currently at an experimental stage (see text for details). C, complement; Del-1, development endothelial locus-1; NSAIDs, non-steroidal anti-inflammatory drugs; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-κB ligand; SPM, specialized pro-resolving mediators; TLR; Toll-like receptor.

Figure 3:. Proinflammatory functions of interleukin-17 with potential for periodontal tissue destruction.

Synergistic complement and Toll-like receptor signaling in antigen-presenting cells enhances interleukin-17 production by adaptive immune cells (Th17). Interleukin-17, in turn, acts predominantly on innate immune and stromal cells to promote inflammatory responses. By upregulating G-CSF, interleukin-17 can orchestrate the production of neutrophils in the bone marrow and their mobilization to the circulation. By inducing CXC chemokines, interleukin-17 can induce the chemotactic recruitment of neutrophils to the periodontium. Additionally, interleukin-17 facilitates neutrophil recruitment by inhibiting negative regulators of the leukocyte adhesion cascade. Specifically, interleukin-17 can inhibit endothelial cell production of Del-1, a homeostatic protein that suppresses neutrophil adhesion and extravasation by blocking the interaction between the LFA-1 integrin on neutrophils and the adhesion molecule ICAM-1 on endothelial cells. Moreover, interleukin-17 activates macrophages and may promote the degradation of both connective tissue and the underlying bone by inducing the production of matrix metalloproteinases and RANKL from stromal cell types.