Kininogens coordinate adaptive immunity through the proteolytic release of bradykinin, an endogenous danger signal driving dendritic cell maturation

Abstract

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. © 2007 The Authors.