Kinin Danger Signals Proteolytically Released by Gingipain Induce Fimbriae-Specific IFN-γ- and IL-17-Producing T Cells in Mice Infected Intramucosally with Porphyromonas gingivalis

Abstract

Porphyromonas gingivalis, a Gram-negative bacterium that causes periodontitis, activates the kinin system via the cysteine protease R-gingipain. Using a model of buccal infection based on P. gingivalis inoculation in the anterior mandibular vestibule, we studied whether kinins released by gingipain may link mucosal inflammation to T cell-dependent immunity through the activation of bradykinin B2 receptors (B2R). Our data show that P. gingivalis W83 (wild type), but not gingipain-deficient mutant or wild-type bacteria pretreated with gingipain inhibitors, elicited buccal edema and gingivitis in BALB/c or C57BL/6 mice. Studies in TLR2−/−, B2R−/−, and neutrophil-depleted C57BL/6 mice revealed that P. gingivalis induced edema through the sequential activation of TLR2/neutrophils, with the initial plasma leakage being amplified by gingipain-dependent release of vasoactive kinins from plasma-borne kininogens. We then used fimbriae (Fim) Ag as a readout to verify whether activation of the TLR2→PMN→B2R axis (where PMN is polymorphonuclear neutrophil) at early stages of mucosal infection had impact on adaptive immunity. Analyzes of T cell recall responses indicated that gingipain drives B2R-dependent generation of IFN-γ-producing Fim T cells in submandibular draining lymph nodes of BALB/c and C57BL/6 mice, whereas IL-17-producing Fim T cells were generated only in BALB/c mice. In summary, our studies suggest that two virulence factors, LPS (an atypical TLR2 ligand) and gingipain, forge a trans-cellular cross-talk between TLR2 and B2R, thus forming an innate axis that guides the development of Fim-specific T cells in mice challenged intrabuccally by P. gingivalis. Ongoing research may clarify whether kinin-driven modulation of T cell responses may also influence the severity of chronic periodontitis.

Periodontal Pathogens Directly Promote Autoimmune Experimental Arthritis by Inducing a TLR2- and IL-1–Driven Th17 Response

“…This is in line with Th17 induction by P. gingivalis in humans and a previous study showing that intramucosal inoculation of P. gingivalis in naive mice can induce a kinin-dependent Th17 phenotype (34,37,38). In addition, increased mRNA expression of T cell-related transcription factors has been shown in submandibular lymph nodes of mice upon coinduction of pristaneinduced arthritis and Agregatibacter actinomycetemcomitansinduced PD (39).…”

“…However, P. gingivalis possesses several other virulence factors such as LPS, fimbriae hemagglutinin, and gingipains as well, which may directly contribute to its pathogenicity regardless of citrullination (33,34). It is also important to consider that PD is in fact a polymicrobial disease.…”

C-reactive protein levels in hereditary angioedema

“…Therefore, the presence of IL-17 during asymptomatic periods could be a possible explanation for CRP increase. Interestingly, IL-17 production can be induced by bradykinin [32,33]. Therefore, we speculate that the slightly increased CRP concentrations in HAE actually reflect increased exposure to bradykinin in asymptomatic as well as during acute attacks due to poor control of contact activation in C1INH deficiency.…”

Periodontal bacteria aggravate experimental autoimmune myocarditis in mice

“…Recent reports assert that Th17 cells play important roles in the pathogenesis of EAM (3,46). The severity of chronic human periodontal disease is positively correlated with IL-17 levels (22,31). P.g.…”