Cooperative activation of TLR2 and bradykinin B2 receptor is required for induction of type 1 immunity in a mouse model of subcutaneous infection by Trypanosoma cruzi.
We have previously reported that exogenous bradykinin activates immature dendritic cells (DCs) via the bradykinin B(2) receptor (B(2)R), thereby stimulating adaptive immunity. In this study, we show that these premises are met in a model of s.c. infection by Trypanosoma cruzi, a protozoan that liberates kinins from kininogens through its major protease, cruzipain. Intensity of B(2)R-dependent paw edema evoked by trypomastigotes correlated with levels of IL-12 produced by CD11c(+) dendritic cells isolated from draining lymph nodes. The IL-12 response induced by endogenously released kinins was vigorously increased in infected mice pretreated with inhibitors of angiotensin converting enzyme (ACE), a kinin-degrading metallopeptidase. Furthermore, these innate stimulatory effects were linked to B(2)R-dependent up-regulation of IFN-gamma production by Ag-specific T cells. Strikingly, the trypomastigotes failed to up-regulate type 1 immunity in TLR2(-/-) mice, irrespective of ACE inhibitor treatment. Analysis of the dynamics of inflammation revealed that TLR2 triggering by glycosylphosphatidylinositol-anchored mucins induces plasma extravasation, thereby favoring peripheral accumulation of kininogens in sites of infection. Further downstream, the parasites generate high levels of innate kinin signals in peripheral tissues through the activity of cruzipain. The demonstration that the deficient type 1 immune responses of TLR2(-/-) mice are rescued upon s.c. injection of exogenous kininogens, along with trypomastigotes, supports the notion that generation of kinin "danger" signals is intensified through cooperative activation of TLR2 and B(2)R. In summary, we have described a s.c. infection model where type 1 immunity is vigorously up-regulated by bradykinin, an innate signal whose levels in peripheral tissues are controlled by an intricate interplay of TLR2, B(2)R, and ACE.
Monteiro
Ana Carolina
AC
Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Centre de Ciências da Saúde, Sala D 007, Rio de Janeiro, Brazil.
Schmitz
Verônica
V
Svensjo
Erik
E
Gazzinelli
Ricardo T
RT
Almeida
Igor C
IC
Todorov
Alex
A
de Arruda
Luciana B
LB
Torrecilhas
Ana Cláudia T
AC
Pesquero
João B
JB
Morrot
Alexandre
A
Bouskela
Eliete
E
Bonomo
Adriana
A
Lima
Ana Paula C A
AP
Müller-Esterl
Werner
W
Scharfstein
Julio
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D039521:CD11c Antigen / Q000032:analysis; D002454:Cell Differentiation; D014355:Chagas Disease / Q000276:immunology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000378:metabolism; D007704:Kininogens / Q000008:administration & dosage / Q000378:metabolism; D007705:Kinins / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D015800:Protozoan Proteins; D043782:Receptor, Bradykinin B2 / Q000819:agonists* / Q000235:genetics; D012867:Skin / Q000276:immunology / Q000469:parasitology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics; D014349:Trypanosoma cruzi
D000806:Angiotensin-Converting Enzyme Inhibitors; D039521:CD11c Antigen; D007704:Kininogens; D007705:Kinins; D015800:Protozoan Proteins; D043782:Receptor, Bradykinin B2; D051195:Toll-Like Receptor 2; D018664:Interleukin-12; D007703:Peptidyl-Dipeptidase A; D003546:Cysteine Endopeptidases; C063214:cruzipain; D001920:Bradykinin