For decades, immunologists have considered the
complement system as a paradigm of a proteolytic cascade that, acting cooperatively with the immune system, enhances host defense against infectious organisms. In recent years, advances made in
thrombosis research disclosed a functional link between activated neutrophils, monocytes, and platelet-driven thrombogenesis. Forging a physical barrier, the
fibrin scaffolds generated by synergism between the extrinsic and intrinsic (contact) pathways of coagulation entrap microbes within microvessels, limiting the systemic spread of
infection while enhancing the clearance of pathogens by activated leukocytes. Insight from mice models of
thrombosis linked
fibrin formation via the intrinsic pathway to the autoactivation of
factor XII (FXII) by negatively charged "contact" substances, such as platelet-derived
polyphosphates and
DNA from neutrophil extracellular traps. Following cleavage by FXIIa, activated
plasma kallikrein (PK) initiates
inflammation by liberating the nonapeptide
bradykinin (BK) from an internal domain of
high molecular weight kininogen (HK). Acting as a paracrine mediator, BK induces vasodilation and increases microvascular permeability via activation of endothelial B2R, a constitutively expressed subtype of
kinin receptor. During
infection, neutrophil-driven extravasation of plasma fuels
inflammation via extravascular activation of the kallikrein-kinin system (KKS). Whether liberated by plasma-borne PK,
tissue kallikrein, and/or microbial-derived
proteases, the short-lived
kinins activate immature dendritic cells via B2R, thus linking the
infection-associated innate immunity/
inflammation to the adaptive arm of immunity. As
inflammation persists, a GPI-linked
carboxypeptidase M removes the C-terminal
arginine from the primary
kinin, converting the B2R agonist into a high-affinity
ligand for B1R, a GPCR subtype that is transcriptionally upregulated in injured/inflamed tissues. As reviewed here, lessons taken from studies of
kinin receptor function in experimental
infections have shed light on the complex proteolytic circuits that, acting at the endothelial interface, reciprocally couple immunity to the proinflammatory KKS.