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Screening Assays to Characterize Novel Endothelial Regulators Involved in the Inflammatory Response
Published on: September 15, 2017
Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia
1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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.
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