Toll gates to periodontal host modulation and vaccine therapy

Abstract

Toll-like receptors (TLRs) are central mediators of innate antimicrobial and inflammatory responses and play instructive roles in the development of the adaptive immune response. Thus when stimulated by certain agonists, TLRs serve as adjuvant receptors that link innate and adaptive immunity. However, when excessively activated or inadequately controlled during an infection, TLRs may contribute to immunopathology associated with inflammatory diseases, such as periodontitis. Moreover, certain microbial pathogens appear to exploit aspects of TLR signalling in ways that enhance their adaptive fitness. The diverse and important roles played by TLRs suggest that therapeutic manipulation of TLR signalling may have implications in the control of infection, attenuation of inflammation, and the development of vaccine adjuvants for the treatment of periodontitis. Successful application of TLR-based therapeutic modalities in periodontitis would require highly selective and precisely targeted intervention. This would in turn necessitate precise characterization of TLR signalling pathways in response to periodontal pathogens, as well as development of effective and specific agonists or antagonists of TLR function and signalling. This review summarizes the current status of TLR biology as it relates to periodontitis, and evaluates the potential of TLR-based approaches for host-modulation therapy in this oral disease.

Fig. 1. P. gingivalis exploits TLR2 inside-out signalling to subvert innate immunity

P. gingivalis activates the high-affinity conformation of CR3 through TLR2 inside-out signalling involving Rac1 and phosphatidylinositol 3-kinase (PI3K) (92, 93). CD14 participates in the pathway as a coreceptor for efficient P. gingivalis-induced TLR2 stimulation, which in parallel activates a distinct nuclear factor-κB-dependent pro-inflammatory/antimicrobial pathway (82, 86). Intriguingly, P. gingivalis can interact with activated CR3 leading to its internalization and outside-in signalling, which via extracellular signal-related kinase 1/2 (ERK1/2) downregulates IL-12 p35 and p40 mRNA expression. This in turn inhibits production of bioactive IL-12 and undermines IL-12-mediated immune clearance of the pathogen (84, 235). Blocking TLR2 would counteract this immune evasion strategy but may also suppress protective nuclear factor-κB-dependent antimicrobial responses. On the other hand, inhibitors of signalling intermediates of the inside-out pathway or antagonists of CR3 may selectively target this immune evasion mechanism. The latter approach (CR3 antagonism) was successfully tested in the mouse periodontitis model (84).

Fig. 2. Inhibition of TLR2-mediated innate immune responses through P. gingivalis exploitation of CXCR4

P. gingivalis instigates a molecular cross-talk between CXCR4 and TLR2 in macrophage lipid rafts. Unlike CD14 which facilitates TLR2 activation by P. gingivalis (86), CXCR4 suppresses TLR2 signalling (89). Specifically, the pathogen binds CXCR4 and induces cAMP-dependent PKA signalling, which in turn inhibits TLR2-mediated nuclear factor-κB activation. This promotes the in vivo survival of the pathogen, unless CXCR4 is blocked by specific antagonists (89).