title: 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.
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 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.
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Monteiro
authors.forename: Aline
authors.initials: A
authors.lastname: Scovino
authors.forename: Susane
authors.initials: S
authors.lastname: Raposo
authors.forename: Vinicius Mussa
authors.initials: VM
authors.lastname: Gaze
authors.forename: Catia
authors.initials: C
authors.lastname: Cruz
authors.forename: Erik
authors.initials: E
authors.lastname: Svensjö
authors.forename: Marcelo Sampaio
authors.initials: MS
authors.lastname: Narciso
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Colombo
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Eduardo
authors.initials: E
authors.lastname: Feres-Filho
authors.forename: Ky-Anh
authors.initials: KA
authors.lastname: Nguyen
authors.forename: Aneta
authors.initials: A
authors.lastname: Sroka
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.forename: Julio
authors.initials: J
authors.lastname: Scharfstein
mesh_terms: 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*
chemical_list: 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
references.citation: J Immunol. 2006 Dec 15;177(12):8296-300
references.pmid: 17142724
references.citation: J Bacteriol. 2007 Feb;189(3):833-43
references.pmid: 17142394
references.citation: Scand J Immunol. 2007 Aug-Sep;66(2-3):128-36
references.pmid: 17635790
references.citation: Peptides. 2004 Mar;25(3):521-5
references.pmid: 15134871
references.citation: J Innate Immun. 2009;1(2):118-22
references.pmid: 20375570
references.citation: J Immunol. 2007 Aug 15;179(4):2359-67
references.pmid: 17675497
references.citation: J Biol Chem. 1997 Jun 20;272(25):16062-7
references.pmid: 9188512
references.citation: Am J Pathol. 2006 Sep;169(3):987-98
references.pmid: 16936272
references.citation: Oral Microbiol Immunol. 2009 Feb;24(1):38-42
references.pmid: 19121068
references.citation: Infect Immun. 1995 May;63(5):1999-2003
references.pmid: 7729914
references.citation: Immunity. 2006 Feb;24(2):179-89
references.pmid: 16473830
references.citation: J Biol Chem. 1994 Jan 7;269(1):406-11
references.pmid: 8276827
references.citation: J Exp Med. 2006 Nov 27;203(12):2673-82
references.pmid: 17088434
references.citation: J Biol Chem. 2005 Nov 25;280(47):38902-13
references.pmid: 16129673
references.citation: Oral Dis. 2008 Mar;14(2):95-101
references.pmid: 18302669
references.citation: J Immunol. 2007 Dec 15;179(12):8274-9
references.pmid: 18056371
references.citation: Infect Immun. 1995 Apr;63(4):1176-82
references.pmid: 7890369
references.citation: J Biol Chem. 1998 Oct 30;273(44):29072-6
references.pmid: 9786913
references.citation: J Dent Res. 2006 Aug;85(8):678-89
references.pmid: 16861283
references.citation: J Immunol. 2003 Jun 1;170(11):5349-53
references.pmid: 12759407
references.citation: Infect Immun. 2004 Sep;72(9):5041-51
references.pmid: 15321997
references.citation: J Vasc Res. 2009;46(5):435-46
references.pmid: 19176972
references.citation: Nat Immunol. 2007 Sep;8(9):967-74
references.pmid: 17581537
references.citation: FASEB J. 2004 Feb;18(2):370-2
references.pmid: 14688199
references.citation: J Biol Chem. 1992 Sep 15;267(26):18902-7
references.pmid: 1527018
references.citation: J Immunol. 2007 Aug 15;179(4):2349-58
references.pmid: 17675496
references.citation: J Clin Periodontol. 2005 Apr;32(4):383-9
references.pmid: 15811056
references.citation: Annu Rev Immunol. 2007;25:821-52
references.pmid: 17201677
references.citation: Front Biosci. 2007 May 01;12:3965-74
references.pmid: 17485350
references.citation: J Biol Chem. 1993 Apr 15;268(11):7935-42
references.pmid: 8385128
references.citation: J Biol Chem. 1992 Sep 15;267(26):18896-901
references.pmid: 1527017
references.citation: Nat Rev Immunol. 2006 Apr;6(4):329-33
references.pmid: 16557264
references.citation: Pharmacol Rev. 2005 Mar;57(1):27-77
references.pmid: 15734727
references.citation: Immunity. 2005 Mar;22(3):285-94
references.pmid: 15780986
references.citation: Infect Immun. 1996 Jun;64(6):1984-91
references.pmid: 8675297
references.citation: Nature. 2006 May 11;441(7090):231-4
references.pmid: 16648837
references.citation: Infect Immun. 2007 Feb;75(2):892-8
references.pmid: 17118977
references.citation: PLoS Pathog. 2007 Nov;3(11):e185
references.pmid: 18052532
references.citation: Biol Chem. 2008 Aug;389(8):1015-24
references.pmid: 18979626
references.citation: J Innate Immun. 2009;1(1):18-28
references.pmid: 20375563
references.citation: Immunity. 2006 Feb;24(2):191-201
references.pmid: 16473831
references.citation: J Immunol. 2006 Nov 1;177(9):6325-35
references.pmid: 17056563
references.citation: J Periodontol. 2007 Aug;78(8):1545-50
references.pmid: 17668974
references.citation: Infect Immun. 1996 Nov;64(11):4788-94
references.pmid: 8890240
references.citation: Microbiol Mol Biol Rev. 1998 Dec;62(4):1244-63
references.pmid: 9841671
references.citation: Clin Rev Allergy Immunol. 1998 Winter;16(4):385-401
references.pmid: 9926287
references.citation: Front Biosci. 2008 Jan 01;13:2041-59
references.pmid: 17981690
references.citation: J Leukoc Biol. 2009 Jun;85(6):1005-14
references.pmid: 19293401
references.citation: Periodontol 2000. 1999 Jun;20:341-62
references.pmid: 10522230
references.citation: Infect Immun. 2004 Mar;72(3):1374-82
references.pmid: 14977941
references.citation: J Dent Res. 2004 Dec;83(12):941-5
references.pmid: 15557402
references.citation: J Immunol. 2007 Dec 1;179(11):7777-90
references.pmid: 18025224
references.citation: Am J Pathol. 2007 Jan;170(1):203-13
references.pmid: 17200194
references.citation: J Dent Res. 2003 Oct;82(10):796-801
references.pmid: 14514759
references.citation: Annu Rev Immunol. 2002;20:795-823
references.pmid: 11861618
references.citation: Nature. 2007 Oct 18;449(7164):819-26
references.pmid: 17943118
references.citation: Infect Immun. 1995 Dec;63(12):4877-82
references.pmid: 7591149
references.citation: J Immunol. 2007 Jun 1;178(11):7242-50
references.pmid: 17513773
references.citation: Biol Chem. 1997 Mar-Apr;378(3-4):223-30
references.pmid: 9165075
references.citation: Infect Immun. 2002 Jun;70(6):3304-7
references.pmid: 12011031
references.citation: J Periodontol. 2004 Jan;75(1):37-43
references.pmid: 15025215
references.citation: Pharmacol Rev. 1992 Mar;44(1):1-80
references.pmid: 1313585
references.citation: J Clin Invest. 1994 Jul;94(1):361-7
references.pmid: 8040277
references.citation: Immunity. 2007 Oct;27(4):660-9
references.pmid: 17919942
references.citation: Cell Microbiol. 2008 May;10(5):1181-9
references.pmid: 18182086