Periodontitis: from microbial immune subversion to systemic inflammation

Abstract

Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites.

Figures

Figure 1. Polymicrobial synergy and dysbiosis in periodontitis

Periodontitis is induced in susceptible hosts by a polymicrobial community, in which different members fulfil distinct roles that converge synergistically to cause destructive inflammation. Keystone pathogens, the colonization of which is facilitated by accessory pathogens, initially subvert the host response leading to a dysbiotic microbiota, in which pathobionts over-activate the inflammatory response and cause periodontal tissue destruction, including resorption of the supporting alveolar bone. Inflammation and dysbiosis positively reinforce each other because inflammatory tissue breakdown products are used as nutrients by the dysbiotic microbiota. The lower panel depicts the progression from periodontal health (swallow gingival crevice; ≤2 mm) to gingivitis (periodontal inflammation without bone loss; gingival crevice ≤3 mm) to periodontitis (formation of periodontal pockets ≥4 mm and inflammatory bone loss). Inflammation-induced collagenolytic enzymes can contribute to loss of tissue attachment to the teeth and the deepening and ulceration of the pockets (up to 10-12 mm covering a surface area of 8-20 cm2), which serve as a niche that can harbour 108 to 1010 bacteria feeding on the inflammatory spoils (for example collagen peptides, haem-containing compounds) carried with the gingival crevicular fluid (GCF) that bathes the pocket.

Figure 2. Porphyromonas gingivalis subversion of neutrophils leads to dysbiotic inflammation

Porphyromonas gingivalis expresses ligands that activate the Toll-like receptor 2 (TLR1)–TLR2 complex and enzymes (HRgpA and RgpB gingipains) with C5 convertase-like activity that generate high local concentrations of C5a ligand. The organism can co-activate C5aR and TLR2 in neutrophils and the resulting crosstalk leads to ubiquitination and proteasomal degradation of the TLR2 adaptor MYD88, thereby inhibiting a host-protective antimicrobial response. This proteolytic event requires C5aR–TLR2-dependent release of transforming growth factor-β (TGF-β1), which mediates MYD88 ubiquitination via the E3 ubiquitin ligase Smurf1 (enlarged inset). Moreover, the C5aR–TLR2 crosstalk activates phosphoinositide 3-kinase (PI3K), which prevents phagocytosis through inhibition of RhoA GTPase and actin polymerization, while stimulating the production of inflammatory cytokines. In contrast to MyD88, another TLR2 adaptor, Mal, contributes to immune subversion by acting upstream of PI3K. These functionally integrated pathways, as manipulated by P. gingivalis, provide ‘bystander’ protection to otherwise susceptible bacterial species and promote polymicrobial dysbiotic inflammation in vivo. C5aR, complement C5a receptor; HRgpA, high molecular mass arginine-specific gingipain A; Mal, MyD88 adaptor-like; MyD88, myeloid differentiation primary response protein 88; RgpB, arginine-specific gingipain B; Smurf1, Smad ubiquitin regulatory factor 1. Reproduced with permission from REF..

Figure 3. Biologically plausible mechanisms linking periodontitis to systemic inflammation and disease

In periodontitis, locally produced pro-inflammatory cytokines can enter the systemic circulation and induce an acute-phase response in the liver — which is characterized by increased levels of C reactive protein, fibrinogen and serum amyloid A — in turn contributing to atherosclerosis or exacerbating intra-uterine inflammation. Moreover, gingival ulceration in periodontal pockets enables the egress and systemic dissemination of periodontal bacteria. Certain bacteria including Porphyromonas gingivalis have been detected in circulating leukocytes and in atherosclerotic lesions, where they may act as pro-atherogenic stimuli. Other periodontal bacteria such as Fusobacterium nucleatum have been detected in the placenta where they can cause adverse pregnancy outcomes. Large quantities of oral bacteria are constantly swallowed on a daily basis via the saliva into the gut. In this context, an alternative, or additional, mechanism linking periodontitis to systemic inflammation was recently proposed: Swallowed P. gingivalis causes alterations to the gut microbiota, thereby leading to increased gut epithelial permeability and endotoxemia, which causes systemic inflammation. Although independent, the depicted events are not mutually exclusive but could in principle occur simultaneously. CRP, C-reactive protein; IL, interleukin; TNF, tumor necrosis factor.

Figure 4. Microbial immune subversion in atherogenesis

In addition to a bacteraemic route, periodontal bacteria may hijack leukocytes or erythrocytes (to which they attach via a C3b–CR1 interaction) to disseminate from the oral mucosa to aortic tissues. Bacteria not only invade but also activate endothelial cells (upregulation of cell adhesion molecules and chemokines) in ways that promote the transmigration of leukocytes that may harbour viable intracellular bacteria. The bacteria can spread to deeper tissues where they can induce smooth-muscle-cell proliferation in the intima. The uptake of low-density lipoprotein (LDL) by transmigrated macrophages is enhanced in the presence of bacteria leading to accelerated foam cell formation and atherogenesis. At later stages, atherosclerotic plaque rupture can be facilitated by bacterially induced production of matrix metalloproteinases (MMPs) by lymphocytes or myeloid cells. Bacteria-induced platelet aggregation (directly or through the induction of prothrombotic autoantibodies) may contribute to thrombotic vessel occlusion. Most of these studies supporting the above-discussed model utilized Porphyromonas gingivalis as model pathogen, the survival of which within leukocytes depends in part upon Toll-like receptor 4 (TLR4) evasion as well as on its capacity to exploit CR3 (in macrophages) or DC-SIGN (in dendritic cells) for safe intracellular entry. Abs, antibodies; CR1, complement receptor-1; CR3, complement receptor-3; DC, dendritic cell; DC-SIGN, DC-specific ICAM-3 grabbing nonintegrin; SMC, smooth muscle cell; TLR4, Toll-like receptor 4.

Figure 5. Porphyromonas gingivalis-mediated citrullination and induction of ACPA in rheumatoid arthritis

P. gingivalis peptidylarginine deiminase (PPAD) citrullinates host-derived or bacterial proteins in the inflammatory environment of periodontitis. In susceptible individuals (carriers of HLA-DRB1 shared epitope (SE) alleles), distinct citrullinated peptides are presented in the context of HLA-DRB1 SE to activate T cells, which, in turn stimulate B-cell production of anti-citrullinated protein antibodies (ACPA). The induction of autoantibodies may be explained by mechanisms involving neoepitope formation or molecular mimicry. Citrullination of host proteins, such as α-enolase, fibrinogen and collagen type II, by human peptidylarginine deiminase (PAD) enzymes can occur in injured or inflamed joints. ACPA bind citrullinated proteins and form immune complexes that can mediate local synovial inflammation by activating complement or Fcγ receptors (FcγR).