Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches

Abstract

The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis.

Figures

Figure 1. The polymicrobial synergy and dysbiosis (PSD) model of periodontal disease pathogenesis

Periodontitis is induced by a polymicrobial bacterial community, wherein different members have distinct roles that synergize to cause destructive inflammation. Keystone pathogens, the colonization of which is facilitated by accessory pathogens, manipulate the host response leading from a symbiotic to a dysbiotic microbiota, in which pathobionts over-activate the inflammatory response and cause destructive resorption of the supporting bone. Inflammation and dysbiosis reinforce each other by engaging in a positive feedback loop (inflammatory tissue breakdown products are used as nutrients by the dysbiotic microbiota, which further exacerbates inflammation). The lower panel shows the progression from periodontal health to gingivitis (gingival inflammation without bone loss) to periodontitis (loss of epithelial attachment, formation of deep periodontal pockets, and inflammatory bone loss). Periodontal pockets serve as a niche that can harbor dysbiotic bacterial communities feeding on the inflammatory spoils (e.g., degraded collagen peptides, haem-containing compounds) transferred with the gingival crevicular fluid (GCF) that bathes the pockets. Redrawn from Ref. [13]. Used by permission.

Figure 2. Complement involvement in periodontal dysbiosis and inflammation

Colonization of the periodontium by P. gingivalis impairs innate host defense by instigating a subversive C5aR-TLR2 crosstalk, which leads to the dysbiotic transformation of the periodontal microbiota. The dysbiotic microbial community in turn causes C3-dependent inflammatory bone loss, the hallmark of periodontitis. The resulting inflammatory environment selects for inflammophilic bacteria that feed on inflammatory breakdown products, thereby promoting further bacterial growth and dysbiosis. These pathologic interactions generate and perpetuate a vicious cycle of periodontal tissue destruction. Modified from Ref. [50] on the basis of recent studies [47, 56]. Used by permission.

Figure 3. Inhibition of complement-dependent host defenses by periodontal bacteria

P. gingivalis (Pg) and P. intermedia (Pi) protect themselves against complement by using surface molecules (HRgpA gingipain for P. gingivalis, undefined molecule for P. intermedia) to capture the circulating C4b-binding protein (C4BP), a physiological negative regulator of the classical and lectin pathways. Treponema denticola (Td) hijacks another regulator, the complement factor H (CFH), using a lipoprotein known as factor H-binding protein (FhbP). In this way, the bacteria can prevent complement-dependent opsonophagocytosis and the formation of the membrane attack complex (MAC). Moreover, although P. gingivalis and T. forsythia proteases can release biologically active C5a from C5 (which leads to immune evasion and inflammation), the generated C5b component is degraded by the same proteases (Arg-specific gingipains HRgpA and RgpB and karilysin), thereby preventing the generation of MAC.