Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

Abstract

Activated protein C (aPC) therapy reduces mortality in adult patients with severe sepsis. In mouse endotoxemia and sepsis models, mortality reduction requires the cell signaling function of aPC, mediated through protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR; also known as Procr). Candidate cellular targets of aPC include vascular endothelial cells and leukocytes. Here, we show that expression of EPCR and PAR1 on hematopoietic cells is required in mice for an aPC variant that mediates full cell signaling activity but only minimal anticoagulant function (5A-aPC) to reduce the mortality of endotoxemia. Expression of EPCR in mature murine immune cells was limited to a subset

Activated Protein C Attenuates Systemic Lupus Erythematosus and Lupus Nephritis in MRL-Fas(lpr) Mice

“…The signaling effects of activated protein C on B cells are still unknown. A recent study discovered that the activation of EPCR on the specific CD8 + subset of spleen dendritic cells is sufficient to suppress immune responses during sepsis and that activated protein C has additional immunosuppressive effects on other dendritic cells in an EPCR-independent manner (38). Our own data are in line with these observations, as recombinant activated protein C reduced the activation of CD4-positive and CD8-positive spleen dendritic cell subsets in MRL-Fas(lpr) mice.…”

The Endothelial Protein C Receptor Supports Tissue Factor Ternary Coagulation Initiation Complex Signaling through Protease-activated Receptors

“…The role of EPCR as a crucial co-receptor for PC activation and aPC-mediated cytoprotective signaling in vascular and immune cells is supported by in vitro and in vivo data (57)(58)(59)(60)(61)(62)(63). However, TF is normally not expressed in the vascular endothelium but co-expressed with EPCR in extravascular cells.…”

Anti-Inflammatory Actions of the Anticoagulant, Activated Protein C

“…Many mechanisms have been described, but the exact manner in which APC affects sepsis patients is unclear. Therapeutic APC can regulate neutrophil migration and extravasation by direct engagement of 1 and 3 integrins (Elphick, 2009), suppress macrophage activation dependent on integrin CD11b/CD18 (Kerschen, 2010), control maturation and activation of CD8 + DCs dependent on EPCR (Kerschen, 2010), and neutralize late-stage inflammatory mediators by degrading nuclear histones from apoptotic cells . A recent Cochrane review suggested that APC should not be used for treating patients with severe sepsis or septic shock and that APC is associated with a higher risk of bleeding (Marti-Carvajal, 2011).…”

“…Bir et al (Bir, 2011) demonstrated that 5A-APC could attenuate lung damage caused by P. aeruginosa in critically ill patients. In addition, 5A-APC inhibits the inflammatory response of conventional dendritic cells independent of EPCR and suppresses IFN-gamma production by natural killer-like dendritic cells (Kerschen, 2010). Recently, an APC variant (APC-L38D/N329Q) was generated with minimal anticoagulant activity, but 5-fold enhanced endothelial barrier protective function and 30-fold improved anti-apoptotic function when compared with wild type APC (Ni, 2011).…”