Angiotensin-converting enzyme limits inflammation elicited by Trypanosoma cruzi cysteine proteases: a peripheral mechanism regulating adaptive immunity via the innate kinin pathway.
Tissue injury by pathogens induces a stereotyped inflammatory response that alerts the innate immune system of the potential threat to host integrity. Here, we review knowledge emerging from investigations of the role of the kinin system in the mechanisms that link innate to the adaptive phase of immunity. Progress in this field started with results demonstrating that bradykinin is an endogenous danger signal that induces dendritic cell (DC) maturation via G protein-coupled bradykinin B2 receptors (B2R). The immunostimulatory role of kinins was recently confirmed in two different mouse models of Trypanosoma cruzi infection, a parasitic protozoan equipped with kinin-releasing cysteine proteases (cruzipain). Infection by the intraperitoneal route showed that DCs from B2R-/- mice (susceptible phenotype) failed to sense kinin 'danger' signals proteolytically released by parasites, explaining why these mutant mice display lower frequencies of interferon-gamma-producing effector T-cells. Studies of the dynamics of inflammation in the subcutaneous model of infection revealed that the balance between cruzipain and angiotensin-converting enzyme, respectively acting as kinin-generating and degrading enzymes, governs extent of DC maturation and TH1 development via the B2R-dependent innate pathway. Studies of the kinin role in immunity may shed light on the relationship between proteolytic networks and the cytokine circuits that guide T-cell development.
Scharfstein
Julio
J
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil. scharf@biof.ufrj.br
Monteiro
Ana Carolina
AC
Schmitz
Veronica
V
Svensjö
Erik
E
D000220:Adaptation, Biological / Q000276:immunology*; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007705:Kinins / Q000276:immunology* / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000276:immunology*
D007705:Kinins; D007703:Peptidyl-Dipeptidase A; D003546:Cysteine Endopeptidases