title: C5a and bradykinin receptor cross-talk regulates innate and adaptive immunity in Trypanosoma cruzi infection.
abstract: Complement and the kallikrein-kinin cascade system are both activated in injured tissues. Little is known about their partnership in the immunopathogenesis of Chagas disease, the chronic infection caused by the intracellular protozoan Trypanosoma cruzi. In this study, we show that pharmacological targeting of the C5a receptor (C5aR) or the bradykinin B2 receptor (B2R) inhibited plasma leakage in hamster cheek pouch topically exposed to tissue culture trypomastigotes (TCTs). Further, angiotensin-converting enzyme inhibitors potentiated TCT-evoked paw edema in BALB/c, C57BL/6, and C5-deficient A/J mice through activation of joint pathways between C5aR/B2R or C3aR/B2R. In addition to generation of C5a and kinins via parasite-derived cruzipain, we demonstrate that macrophages internalize TCTs more efficiently through joint activation of C5aR/B2R. Furthermore, we found that C5aR targeting markedly reduces NO production and intracellular parasitism in macrophages. We then studied the impact of C5aR/B2R cross-talk in TCT infection on the development of adaptive immunity. We found that IL-12p40/70 expression was blunted in splenic dendritic cells by blocking either C5aR or B2R, suggesting that codominant signaling via C5aR and B2R fuels production of the Th1-polarizing cytokine. Finally, we assessed the impact of kinins and C5a liberated in parasite-laden tissues on Th cell differentiation. As predicted, BALB/c mice pretreated with angiotensin-converting enzyme inhibitors potentiated IFN-γ production by Ag-specific T cells via C5aR/B2R cross-talk. Interestingly, we found that B2R targeting upregulated IL-10 secretion, whereas C5aR blockade vigorously stimulated IL-4 production. In summary, we describe a novel pathway by which C5aR/B2R cross-talk couples transendothelial leakage of plasma proteins to the cytokine circuitry that coordinates antiparasite immunity.
authors.affiliation: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941, Brazil; Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040, Brazil;
authors.forename: Veronica
authors.initials: V
authors.lastname: Schmitz
authors.affiliation: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941, Brazil;
authors.forename: Larissa Nogueira
authors.initials: LN
authors.lastname: Almeida
authors.affiliation: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941, Brazil;
authors.forename: Erik
authors.initials: E
authors.lastname: Svensjö
authors.affiliation: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941, Brazil;
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Monteiro
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, Lübeck 23538, Germany; and Division of Immunobiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229 jscharf2@gmail.com joerg.koehl@uksh.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.affiliation: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941, Brazil; jscharf2@gmail.com joerg.koehl@uksh.de.
authors.forename: Julio
authors.initials: J
authors.lastname: Scharfstein
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015936:Complement C5a / Q000235:genetics / Q000276:immunology; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015800:Protozoan Proteins; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology*; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D014349:Trypanosoma cruzi / Q000235:genetics / Q000276:immunology*
chemical_list: D000953:Antigens, Protozoan; C000591759:C5ar1 protein, mouse; D016207:Cytokines; D015800:Protozoan Proteins; D044087:Receptor, Anaphylatoxin C5a; D043782:Receptor, Bradykinin B2; D015936:Complement C5a; D003546:Cysteine Endopeptidases; C063214:cruzipain