Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response

Abstract

Recent studies have uncovered novel mechanisms underlying the breakdown of periodontal host-microbe homeostasis, which can precipitate dysbiosis and periodontitis in susceptible hosts. Dysbiotic microbial communities of keystone pathogens and pathobionts are thought to exhibit synergistic virulence whereby not only can they endure the host response but can also thrive by exploiting tissue-destructive inflammation, which fuels a self-feeding cycle of escalating dysbiosis and inflammatory bone loss, potentially leading to tooth loss and systemic complications. Here, I discuss new paradigms in our understanding of periodontitis, which may shed light into other polymicrobial inflammatory disorders. In addition, I highlight gaps in knowledge required for an integrated picture of the interplay between microbes and innate and adaptive immune elements that initiate and propagate chronic periodontal inflammation.

Keywords: dysbiosis; inflammation; keystone pathogen; pathobiont; periodontitis.

Fig. 1. Polymicrobial synergy and dysbiosis in susceptible hosts causes periodontitis.

Periodontal health requires a controlled inflammatory state that can maintain host-microbe homeostasis in the periodontium. However, defects in the immuno-inflammatory status of the host or predisposing conditions and environmental factors (collectively defining a ‘susceptible host’) can shift the balance towards dysbiosis, a state in which former commensals behave as pro-inflammatory pathobionts. The presence of keystone pathogens can similarly tip the balance toward dysbiosis even in hosts without apparent predisposing genetic or environmental factors (at least in mice). The inflammation caused by the dysbiotic microbiota depends in great part on crosstalk signaling between complement and PRRs and has two major and interrelated effects: it causes inflammatory destruction of periodontal tissue (including bone loss, the hallmark of periodontitis) which in turn provides nutrients (tissue breakdown peptides and other products) that further promote dysbiosis and hence tissue destruction, thereby generating a self-perpetuating pathogenic cycle. It should be noted that host susceptibility might not simply be a determinant of the transition from a symbiotic to a dysbiotic microbiota but it may also underlie the predisposition of the host to develop inflammation sufficient to cause irreversible tissue damage. For instance, at least in principle, there might be individuals who can tolerate the conversion of a symbiotic microbiota into a dysbiotic state (such hosts would be susceptible to dysbiosis but not to periodontal bone loss).

Fig. 2. Inflammatory mechanisms leading to bone loss in periodontitis.

Recruited neutrophils to the gingival crevice fail to control a dysbiotic microbiota, which can thus invade the connective tissue and interact with additional immune cell types, such as macrophages (Mφ), dendritic cells (DC), and γδ T cells, a subset of innate-like lymphocytes. These cells produce proinflammatory mediators (such as the bone-resorptive cytokines TNF, IL-1β, and IL-17) and also regulate the development of Th cell types, which also contribute to and exacerbate the inflammatory response. IL-17, a signature cytokine of Th17 (though also produced by innate cell sources), acts on innate immune and connective tissue cell types, such as neutrophils, fibroblasts, and osteoblasts. Through these interactions, IL-17 induces the production of CXC chemokines (which recruit neutrophils in a Del-1–dependent manner), matrix metalloproteinases (MMPs) and other tissue-destructive molecules (e.g., ROS), as well as osteoblast expression of RANKL, which drives the maturation of osteoclast precursors (OCP). Activated lymphocytes (B and T cells, specifically Th1 and Th17) play a major role in pathologic bone resorption through the same RANKL-dependent mechanism, whereas osteoprotegerin (OPG) is a soluble decoy receptor that inhibits the interaction of RANKL with its functional receptor (RANK) on OCP. The RANKL/OPG ratio increases with increasing inflammatory activity. Activated neutrophils express membrane-bound RANKL and could directly stimulate osteoclastogenesis if they are within sufficient proximity to the bone. The anti-inflammatory cytokine IL-10 (produced by Tregs), as well as IFNγ (produced by Th1 cells) and IL-4 plus IL-13 (produced by Th2 cells) can suppress osteoclastogenesis. The innate-adaptive cell interplay is considerably more complex than depicted here but serves to illustrate major destructive mechanisms operating in the context of unresolved periodontal infection and inflammation.

Fig. 3. Cellular cross-talk interactions of Th17 that can shift the balance towards periodontitis.

Bacterially induced IL-23 production by periodontal innate immune cells, such as dendritic cells (DC) and macrophages (Mφ), can not only promote the survival and expansion of Th17 cells but additionally activate γδ T cells in ways that restrain Tregs and shift the balance in favor of Th17 cells. Acting as a link between innate and adaptive immunity, Th17 secrete IL-17 which, by acting mainly through fibroblast upregulation of G-CSF and CXC chemokines, can orchestrate bone marrow production and release of neutrophils and their chemotactic recruitment to the periodontium. Recruited neutrophils, in turn, can produce CCL2 and CCL20 chemokines, which can selectively recruit more Th17 cells by acting on Th17-expressed CCR2 and CCR6. These cellular crosstalk interactions can sustain a positively reinforced feedback for high-level production of IL-17 (possibly also expressed by the neutrophils themselves, according to some studies) sufficient to tip the balance from host protection to inflammatory periodontitis.