The C5a Receptor Impairs IL-12–Dependent Clearance of Porphyromonas gingivalis and Is Required for Induction of Periodontal Bone Loss

Abstract

The C5a anaphylatoxin receptor (C5aR; CD88) is activated as part of the complement cascade and exerts important inflammatory, antimicrobial, and regulatory functions, at least in part, via crosstalk with TLRs. However, the periodontal pathogen Porphyromonas gingivalis can control C5aR activation by generating C5a through its own C5 convertase-like enzymatic activity. In this paper, we show that P. gingivalis uses this mechanism to proactively and selectively inhibit TLR2-induced IL-12p70, whereas the same pathogen-instigated C5aR-TLR2 crosstalk upregulates other inflammatory and bone-resorptive cytokines (IL-1β, IL-6, and TNF-α). In vivo, the ability of P. gingivalis to manipulate TLR2 activation via the C5a-C5aR axis allowed it to escape IL-12p70–dependent immune clearance and to cause inflammatory bone loss in a murine model of experimental periodontitis. In the latter regard, C5aR-deficient or TLR2-deficient mice were both resistant to periodontal bone loss, in stark contrast with wild-type control mice, which is consistent with the interdependent interactions of C5aR and TLR2 in P. gingivalis immune evasion and induction of bone-resorptive cytokines. In conclusion, P. gingivalis targets C5aR to promote its adaptive fitness and cause periodontal disease. Given the current availability of safe and effective C5aR antagonists, pharmacological blockade of C5aR could act therapeutically in human periodontitis and reduce associated systemic risks.

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

“…3A, 3B). This is consistent with literature indicating that IL-10 attenuates IL-6 and TNF production from activated macrophages (34,35). A neutralizing Ab against human IL-10 (10 mg/ml) completely blocked the effect of exogenously added IL-10 (2 ng/ml) in macrophages (Supplemental Fig.…”

“…There is evidence in support of C5aR/TLR crosstalk being exploited by some pathogens for host subversion (12,35). Therefore, the impact of C5a on the ability of HMDMs to clear S. Typhimurium was examined.…”

C5aR-dependent cell activation by physiological concentrations of C5a-desArg: Insights from a novel label-free cellular assay

“…Notably, it is well appreciated that the activation of G αs proteins counteracts the effects induced by G αi proteins and vice versa, especially when it comes to the regulation of intracellular levels of cyclic adenosine monophosphate (cAMP) (50). C5a has been previously shown to modulate the intracellular levels of cAMP in negative and positive manners (46,51). Such apparent controversy may rely on the different cell types (which express different classes of G α proteins) and ligand concentrations used in these studies.…”

“…Although C5a desArg is often considered an "inactivation" product of C5a, a natural variation in responses to C5a and C5a desArg have been observed in the past. Both C5a and C5a desArg bear similar efficacy at inducing histamine and leukotriene C4 release by primed basophils (8), calcium mobilization in mouse peritoneal macrophages (46) and neutrophil-mediated platelet aggregation (47). Further, both proteins are able to prime macrophages and enhance their susceptibility to HIV infection (48).…”

Antimicrobial activity of ethylene-vinyl acetate containing bioactive filler against oral bacteria

“…In accord with this last report, we observed that EVA containing S-PRG filler inhibited the growth of S. mutans and the formation of biofilms in an S-PRG filler content-dependent manner. Yoneda et al have reported that S-PRG filler suppresses the proteolytic activity of gingipains 25) , the enzymes classified as cysteine proteinases, playing a major role in the pathogenesis of periodontitis 35) . The gingipains have an important role in the growth of P. gingivalis 36) .…”