Protease-activated receptors (PARs) are G protein-coupled receptors that are activated by proteolytical cleavage of the amino-terminus and thereby act as sensors for extracellular proteases. While coagulation proteases activate PARs to regulate hemostasis, thrombosis, and cardiovascular function, PAR2 is also activated in extravascular locations by a broad array of serine proteases, including trypsin, tissue kallikreins, coagulation factors VIIa and Xa, mast cell tryptase, and transmembrane serine proteases. Administration of PAR2-specific agonistic and antagonistic peptides, as well as studies in PAR2 knockout mice, identified critical functions of PAR2 in development, inflammation, immunity, and angiogenesis. Here, we review these roles of PAR2 with an emphasis on the role of coagulation and other extracellular protease pathways that cleave PAR2 in epithelial, immune, and neuronal cells to regulate physiological and pathophysiological processes.

Defining critical points of modulation across heterogeneous clinical syndromes may provide insight into new therapeutic approaches. Coagulation initiated by the cytokine-receptor family member known as tissue factor is a hallmark of systemic inflammatory response syndromes in bacterial sepsis and viral haemorrhagic fevers1, 2, and anticoagulants can be effective in severe sepsis with disseminated intravascular coagulation3. The precise mechanism coupling coagulation and inflammation remains unresolved4, 5, 6, 7. Here we show that protease-activated receptor 1 (PAR1) signalling sustains a lethal inflammatory response that can be interrupted by inhibition of either thrombin or PAR1 signalling. The sphingosine 1-phosphate (S1P) axis is a downstream component of PAR1 signalling, and by combining chemical and genetic probes for S1P receptor 3 (S1P3) we show a critical role for dendritic cell PAR1–S1P3 cross-talk in regulating amplification of inflammation in sepsis syndrome. Conversely, dendritic cells sustain escalated systemic coagulation and are the primary hub at which coagulation and inflammation intersect within the lymphatic compartment. Loss of dendritic cell PAR1–S1P3 signalling sequesters dendritic cells and inflammation into draining lymph nodes, and attenuates dissemination of interleukin-1β to the lungs. Thus, activation of dendritic cells by coagulation in the lymphatics emerges as a previously unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses.