title: 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 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.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS, Laboratório de Imunologia Molecular, Cidade Universitária Rio de Janeiro, Rio de Janeiro, Brazil. scharf@biof.ufrj.br
authors.forename: J
authors.initials: J
authors.lastname: Scharfstein
authors.forename: V
authors.initials: V
authors.lastname: Schmitz
authors.forename: E
authors.initials: E
authors.lastname: Svensjö
authors.forename: A
authors.initials: A
authors.lastname: Granato
authors.forename: A C
authors.initials: AC
authors.lastname: Monteiro
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D003713:Dendritic Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007110:Immunity, Active; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007704:Kininogens / Q000378:metabolism / Q000502:physiology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018836:Inflammation Mediators; D007704:Kininogens; D010447:Peptide Hydrolases; D001920:Bradykinin