The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

Abstract

Inflammation and coagulation are closely linked interdependent processes. Under physiologic conditions, the tissue microcirculation functions in anticoagulant and anti-inflammatory fashions. However, when inflammation occurs, coagulation is also set in motion and actively participates in enhancing inflammation. Recently, novel and unexpected roles of hemostasis in the humoral and cellular components of innate immunity have been described. In particular, the protein C system, besides its well-recognized role in anticoagulation, plays a crucial role in inflammation. Indeed, the protein C system is now emerging as a novel participant in the pathogenesis of acute and chronic inflammatory diseases, such as sepsis, asthma, inflammatory bowel disease, atherosclerosis, and lung and heart inflammation, and may emerge as unexpected therapeutic targets for intervention.

Figure 1

Functions of aPC in humoral and cellular innate immunity. After activation of PC, a portion of aPC dissociates from EPCR and binds to phospholipid membranes, probably in lipid rafts, where it exerts anticoagulant effects directly via inactivation of FVa and FVIIIa. By down-regulating thrombin levels, aPC enhances fibrinolysis through down-regulation of activated TAFI, as well as by inactivating the fibrinolytic inhibitor PAI-1. PS is a cofactor for these humoral processes. aPC also binds to cellular receptors, depending on the cell type, for example, EPCR in endothelial cells, various integrins in macrophages and neutrophils, and LRP8 in platelets and monocytes; this complex activates PAR-1, which in turn can cross-activate S1P1, probably via intracellular up-regulation of SphK1 and outward migration of S1P. These steps cause a variety of cytoprotective cellular processes indicated in the box below the schematic.

Figure 2

The PC system in inflammatory disease. The PC pathway plays an important role in several human inflammatory conditions. Members of the PC pathway are down-regulated in patients with these diseases, and therapeutic efficacy has been observed for biologic therapeutics that modulate the PC pathway. (A) IBD. (B) Atherosclerosis. (C) RA. (D) Glomerulonephritis. (E) Asthma.

Figure 3

Links between hemostasis and innate immunity in sepsis. The invading pathogenic agent (in this example, LPS) binds to TLR4 on peripheral monocytes to initiate the hyperinflammatory and hypercoagulable cascades, as diagrammed. EC indicates endothelial cells; aEC, activated endothelial cells; TJ, intercellular tight junction proteins; Ne, neutrophils; Mo, monocytes; Mϕ, macrophages; aTAFI, activated thrombin activatable fibrinolytic inhibitor; and iNOS, inducible nitric acid synthetase. ↑ indicates up-regulation; ↓, down-regulation.