Kinin danger signals proteolytically released by gingipain induce Fimbriae-specific IFN-gamma- and IL-17-producing T cells in mice infected intramucosally with Porphyromonas gingivalis.
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 B(2) receptors (B(2)R). 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(-/-), B(2)R(-/-), 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-->B(2)R 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 B(2)R-dependent generation of IFN-gamma-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 B(2)R, 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.
Monteiro
Ana Carolina
AC
Carlos Chagas Filho Institute of Biophysics, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Scovino
Aline
A
Raposo
Susane
S
Gaze
Vinicius Mussa
VM
Cruz
Catia
C
Svensjö
Erik
E
Narciso
Marcelo Sampaio
MS
Colombo
Ana Paula
AP
Pesquero
João B
JB
Feres-Filho
Eduardo
E
Nguyen
Ky-Anh
KA
Sroka
Aneta
A
Potempa
Jan
J
Scharfstein
Julio
J
D018829:Adhesins, Bacterial / Q000378:metabolism*; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D010861:Fimbriae, Bacterial / Q000276:immunology*; D000080867:Gingipain Cysteine Endopeptidases; D007109:Immunity; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D007705:Kinins / Q000378:metabolism*; D051379:Mice; D009061:Mouth Mucosa / Q000382:microbiology / Q000473:pathology; D010447:Peptide Hydrolases; D016966:Porphyromonas gingivalis / Q000276:immunology*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D018829:Adhesins, Bacterial; D000080867:Gingipain Cysteine Endopeptidases; D020381:Interleukin-17; D007705:Kinins; D043782:Receptor, Bradykinin B2; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D007371:Interferon-gamma; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases
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