Kininogens Coordinate Adaptive Immunity through the Proteolytic Release of Bradykinin, an Endogenous Danger Signal Driving Dendritic Cell Maturation

• Published in: Scandinavian journal of immunology 2007-08, Vol.66 (2-3), p.128-136
• Main Authors: Scharfstein, J, Schmitz, V, Svensjö, E, Granato, A, Monteiro, A.C
• Format: Article
• Language: English
• Subjects: Animals; Bradykinin - metabolism; Bradykinin - secretion; Cell Differentiation - immunology; Dendritic Cells - enzymology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Humans; Immunity, Active; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Kininogens - metabolism; Kininogens - physiology; Peptide Hydrolases - metabolism; Signal Transduction - immunology; Trypanosoma cruzi
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1111/j.1365-3083.2007.01983.x

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 B₂ receptors (B₂R). The premise that immature DC might sense kinin-releasing pathogens through B₂R 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 B₂R, 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.