Complement and periodontitis

Abstract

Although the complement system is centrally involved in host defense, its overactivation or deregulation (e.g., due to inherent host genetic defects or due to pathogen subversion) may excessively amplify inflammation and contribute to immunopathology. Periodontitis is an oral infection-driven chronic inflammatory disease which exerts a systemic impact on health. This paper reviews evidence linking complement to periodontal inflammation and pathogenesis. Clinical and histological observations show a correlation between periodontal inflammatory activity and local complement activation. Certain genetic polymorphisms or deficiencies in specific complement components appear to predispose to increased susceptibility to periodontitis. Animal model studies and in vitro experiments indicate that periodontal bacteria can either inhibit or activate distinct components of the complement cascade. Porphyromonas gingivalis, a keystone species in periodontitis, subverts complement receptor 3 and C5a anaphylatoxin receptor signaling in ways that promote its adaptive fitness in the presence of non-productive inflammation. Overall, available evidence suggests that complement activation or subversion contributes to periodontal pathogenesis, although not all complement pathways or functions are necessarily destructive. Effective complement-targeted therapeutic intervention in periodontitis would require determining the precise roles of the various inductive or effector complement pathways. This information is essential as it may reveal which specific pathways need to be blocked to counteract microbial evasion and inflammatory pathology or, conversely, kept intact to promote host immunity.

Fig. 1. Activation and regulation of the complement system

All three pathways converge at the third component of complement (C3) which is activated by pathway-specific C3 convertases [1]. The classical pathway is initiated by antigen-antibody (Ag-Ab) complexes and requires the participation of C1, C2, and C4. The lectin pathway is triggered through interaction of the mannose-binding lectin (MBL) with specific microbial carbohydrate groups, followed by activation of MBL-associated serine proteases (MASPs) and cleavage of C2 and C4. The alternative pathway is initiated by spontaneously hydrolyzed C3 [C3(H₂O)] which can thereby form a complex with factor B (fB), followed by fB cleavage by factor D (fD) and formation of the initial alternative pathway C3 convertase [1]. Morerover, the alternative pathway can be induced by bacterial lipopolysacharide and lipooligosacharide in a properdin-dependent way [38]. Proteolytic cleavage of a series of proteins downstream of C3 leads to the generation of potent effector molecules. These include the inflammatory anaphylatoxins C3a and C5a, which activate specific receptors (C3aR and C5aR, respectively), although C5a also interacts with the so-called C5a receptor-like 2 (C5L2), which appears to mediate both regulatory and proinflammatory effects [–44]. In the terminal pathway, C5b initiates the assembly of the C5b-9 membrane attack complex (MAC), which in turn induces microbial cell lysis [1] or host cell signaling at sublytic concentrations [78, 168]. Complement activation is regulated at multiple steps by various regulatory proteins, as indicated by the characteristic inhibitory symbols. C1NH, C1 inhibitor; C4BP, C4b-binding protein; CR1; complement receptor 1; DAF, decay accelerating factor; fH, factor H; FHR-1, fH-related protein 1.

Fig. 2. Chemotactic recruitment of inflammatory cells in the gingival crevice

Inflammatory cells, the majority of which are neutrophils, are recruited to the gingival crevice in response to chemotactic signals such as the complement anaphylatoxin C5a [71, 73, 74], which can be generated either immunologically or through microbial action [87, 150]. Although gingival crevicular neutrophils form what looks like a “defense wall” against the tooth-associated bacteria, they largely fail to control the infection and may cause collateral inflammatory tissue damage [, , –144]. The cartoon (on the left) represents magnification of the demarcated tooth area on the right.

Fig. 3. Complement cross-talk pathways and their exploitation by P. gingivalis

P. gingivalis is recognized by the CD14/TLR2/TLR1 receptor complex [106]. This interaction induces PI3K-dependent inside-out signaling, which induces the high-affinity conformation of CR3 [113, 169]. Once in the high-affinity state, CR3 binds P. gingivalis leading to induction of ERK1/2 signaling. This in turn downregulates IL-12 p35 and p40 mRNA expression [119], possibly through suppression of critical transcription factors (the interferon regulatory factors 1 and 8; IRF-1, −8), required for the expression of IL-12 family cytokines [129]. This suppressive effect is specific for IL-12 since induction of proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) is upregulated. Inhibition of bioactive IL-12 through this mechanism in vivo results in impaired immune clearance of P. gingivalis [119]. Moreover, P. gingivalis uses its gingipains to attack C5 and release biologically C5a [87, 150]. Upon C5aR binding, C5a stimulates Gαi-dependent intracellular Ca²⁺ signaling which synergistically enhances the otherwise weak cAMP responses induced by TLR2/TLR1 activation alone. The ensuing activation of the cAMP-dependent protein kinase A (PKA) pathway inactivates glycogen synthase kinase-3β (GSK3β) and impairs the inducible nitrogen synthase (iNOS)-dependent killing of the pathogen in macrophages in vitro and in vivo [87] .