Non‐hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia

Abstract

Summary Background: Activated protein C (APC) protects the host from severe sepsis. Endothelial protein C receptor (EPCR) is expressed on both hematopoietic leukocytes and non‐hematopoietic endothelium, and plays a key role in protein C activation.Objectives: We explore the influence of EPCR deletion on the responses to lipopolysaccharide (LPS) and then determine whether the observed differences are due to loss of hematopoietic or non‐hematopoietic EPCR.Methods and results: After LPS challenge, EPCR null (Procr−/−) mice exhibited more thrombin and cytokine generation, neutrophil sequestration in the lung and a higher mortality rate than Procr+/− mice. Procr+/− BM/Procr−/− (non‐hematopoietic Procr−/−) and Procr−/− BM/Procr+/− (hematopoietic Procr−/−) chimeric mice were generated by bone marrow (BM) transplantation. Compared with control Procr+/− mice, non‐hematopoietic Procr−/− mice exhibited reduced protein C activation by thrombin and exaggerated responses to LPS challenge, whereas Procr+/− mice and hematopoietic Procr−/− mice exhibited similar protein C activation by thrombin and similar responses to LPS challenge.Conclusions: EPCR deletion exaggerates the host responses to LPS primarily due to deficiency of EPCR on the non‐hematopoietic cells.

Activated Protein C Up-Regulates IL-10 and Inhibits Tissue Factor in Blood Monocytes

“…Thus, in our monocyte model, the upregulation of IL-10 by recombinant activated protein C appears to be independent of EPCR. Consistent with this finding, studies by Zheng et al (49) demonstrated that deficiency of EPCR in nonhematopoietic cells (i.e., vascular endothelial cells) exaggerated the host responses to LPS, whereas deficiency of EPCR in hematopoietic leukocytes played a much less important role (49). Furthermore, recent reports demonstrate that recombinant activated protein C can induce a cell signaling response via ERK activation through a PAR-1/S1P1-dependent, but EPCR-independent, mechanism (50).…”

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.…”

The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b

“…However, the mechanism underlying its antiinflammatory function is poorly understood, particularly in regard to the involvement of its receptor, EPCR (12,(14)(15)(16)(17)(18). Here, we report our evidence, using LPS-induced lethal endotoxemia as a model of sepsis in mice, that the efficacy of APC as an effective antiinflammatory agent toward activated macrophages is critically dependent on integrin CD11b/CD18.…”