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Kininogens Coordinate Adaptive Immunity through the Proteolytic Release of Bradykinin, an Endogenous Danger Signal Driving Dendritic Cell Maturation
Author(s) -
Scharfstein J.,
Schmitz V.,
Svensjö E.,
Granato A.,
Monteiro A. C.
Publication year - 2007
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2007.01983.x
Subject(s) - endogeny , bradykinin , proteolytic enzymes , microbiology and biotechnology , immunity , acquired immune system , chemistry , immunology , biology , biochemistry , immune system , enzyme , receptor
Strategically positioned in peripheral tissues, immune sentinel cells sense microbes and/or their shed products through different types of pattern‐recognition receptors. Upon secretion, pre‐formed pro‐inflammatory mediators activate the microvasculature, inducing endothelium/neutrophil adherence and impairing endothelium barrier function. As plasma proteins enter into peripheral tissues, short‐lived proinflammatory peptides are rapidly generated by limited proteolysis of complement components and the kininogens (i.e. kinin‐precursor proteins). While much emphasis has been placed on the studies of the vascular functions of kinins, their innate effector roles remain virtually unknown. A few years ago, we reported that exogenous bradykinin (BK) potently induces dendritic cell (DC) maturation, driving IL‐12‐dependent Th1 responses through the activation of G‐protein‐coupled BK B 2 receptors (B 2 R). The premise that immature DC might sense kinin‐releasing pathogens through B 2 R was demonstrated in the subcutaneous mouse model of Trypanosoma cruzi infection. Analysis of the dynamics of parasite‐evoked inflammation revealed that activation of TLR2/neutrophils drives the influx of plasma proteins, including kininogens, into peripheral tissues. Once associated to cell surfaces and/or extracellular matrices, the surface‐bound kininogens are cleaved by T. cruzi cysteine proteases. Acting as short‐lived ‘danger’ signals, kinins activate DC via B 2 R, converting them into Th1 inducers. Fine tuned control of the extravascular levels of these natural peptide adjuvants is exerted by kinin‐degrading metallopeptidases, e.g. Angiotensin converting enzyme (ACE/CD143). In summary, the studies in the subcutaneous model of T. cruzi infection revealed that the peripheral levels of BK, a DC maturation signal, are controlled by TLR2/neutrophils and ACE, respectively characterized as positive and negative modulators of innate/adaptive immunity.