Protease Signaling in Severe Systemic Inflammation.

The tissue factor (TF) pathway drives disseminated intravascular coagulation in sepsis. Although extensive in vitro data demonstrate proinflammatory effects of protease activated receptor (PAR) signaling, it remains unclear whether PAR signaling plays a significant role in severe systemic inflammation. In a murine model of severe, 75–90% lethal endotoxemia, we addressed the interplay between intravascular coagulation activation (based on thrombin-antithrombin complexes) and inflammatory exacerbation (based on inflammatory cytokines IL6, IL1b and MCP1) downstream of PAR signaling. TF cytoplasmic domain deleted mice displayed increased TF expression in macrophages and enhanced systemic coagulation activation. However, these mice resolved inflammation earlier than wild-type controls. Thus, intravascular coagulation activation per se does not predict survival. Rather, genetic deletion of PAR2 demonstrated that PAR2 signaling increased survival in TF cytoplasmic domain-deleted mice. PAR2 deficiency alone initially attenuated inflammatory cytokine production, but did not prevent progressive exacerbation of coagulation and inflammation, further evidence for protective PAR2 signaling in advanced, severe endotoxemia. In contrast, PAR1-deficiency had no effect on initial inflammation and coagulation, but at late stages attenuated inflammation and prolonged survival. In addition, PAR1-deficiency produced a synergistic survival benefit with TF cytoplasmic domain deletion. These experiments show that coagulation protease signaling both regulates and amplifies severe systemic inflammation. Strategies to target TF cytoplasmic domain signaling may therefore be beneficial to reduce sepsis lethality in combination with therapeutic blockade of proinflammatory PAR1 signaling.