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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900895v1 183/6/3700    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Monteiro, A. C. Articles by Scharfstein, J. PubMed PubMed Citation Articles by Monteiro, A. C. Articles by Scharfstein, J.

Kinin Danger Signals Proteolytically Released by Gingipain Induce Fimbriae-Specific IFN-- and IL-17-Producing T Cells in Mice Infected Intramucosally with Porphyromonas gingivalis¹

Ana Carolina Monteiro^*, Aline Scovino^*, Susane Raposo^*,, Vinicius Mussa Gaze^*,, Catia Cruz^*, Erik Svensjö^*, Marcelo Sampaio Narciso, Ana Paula Colombo, João B. Pesquero^¶, Eduardo Feres-Filho, Ky-Anh Nguyen^||,#, Aneta Sroka^**, Jan Potempa^**, and Julio Scharfstein^2,*

^* Carlos Chagas Filho Institute of Biophysics, Faculty of Odontology, Department of Histology, Institute of Biomedical Sciences, and Pablo de Góes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; ^¶ Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil; ^|| Institute of Dental Research, Westmead Millenium Institute and ^# Faculty of Dentistry, University of Sydney, Sydney, Australia; ^** Faculty of Biochemistry, Biophysics, and Biotechnology, Department of Microbiology, Jagiellonian University, Krakow, Poland; and Department of Periodontics, University of Louisville School of Dentistry, Louisville, KY 40202

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 TLR2PMNB₂R 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--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Instituto Nacional de Pesquisa em Biologia Estrutural e Bio-Imagem do Conselho Nacional de Desenvolvimento Científico e Tecnológico), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro/Programa Pensa Rio, and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, National Institutes of Health Grants DE 09761 and 1642/B/P01/2008/35, and a grant from the Department of Scientific Research, Polish Ministry of Science and Education.

² Address correspondence and reprint requests to Dr. Julio Scharfstein, Universidade Federal do Rio de Janeiro, Centro de Ciencias de Saude, Ilha do Fundao, Bloco D, Sala D 007, Rio de Janeiro, Rio de Janeiro 21944-900, Brazil. E-mail address: scharf{at}biof.ufrj.br

³ Abbreviations used in this paper: Fim, fimbriae; BK, bradykinin; B₂R, BK B₂ receptor; DC, dendritic cell; HCP, hamster cheek pouch; HK, human kininogen; LBK, lysyl-BK; LN, lymph node; NOD, nucleotide-binding oligomerization domain; p.i., postinfection; PMN, polymorphonuclear neutrophil; Rgps, arginine-specific gingipain; TAFI, thrombin-activatable fibrinolysis inhibitor; WT, wild type.

⁴ The online version of this article contains supplemental material.