Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest 2010 Sep;120(9):3167-78
Date
08/18/2010Pubmed ID
20714108Pubmed Central ID
PMC2929901DOI
10.1172/JCI42629Scopus ID
2-s2.0-77956372381 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
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 of CD8+ conventional dendritic cells. Adoptive transfer of splenic CD11chiPDCA-1- dendritic cells from wild-type mice into animals with hematopoietic EPCR deficiency restored the therapeutic efficacy of aPC, whereas transfer of EPCR-deficient CD11chi dendritic cells or wild-type CD11chi dendritic cells depleted of EPCR+ cells did not. In addition, 5A-aPC inhibited the inflammatory response of conventional dendritic cells independent of EPCR and suppressed IFN-gamma production by natural killer-like dendritic cells. These data reveal an essential role for EPCR and PAR1 on hematopoietic cells, identify EPCR-expressing dendritic immune cells as a critical target of aPC therapy, and document EPCR-independent antiinflammatory effects of aPC on innate immune cells.
Author List
Kerschen E, Hernandez I, Zogg M, Jia S, Hessner MJ, Fernandez JA, Griffin JH, Huettner CS, Castellino FJ, Weiler HAuthors
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of WisconsinHartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnticoagulants
CD8-Positive T-Lymphocytes
Dendritic Cells
Endothelial Cells
Endotoxemia
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein C
Sepsis
Signal Transduction