Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice.
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.
Kerschen
Edward
E
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Hernandez
Irene
I
Zogg
Mark
M
Jia
Shuang
S
Hessner
Martin J
MJ
Fernandez
Jose A
JA
Griffin
John H
JH
Huettner
Claudia S
CS
Castellino
Francis J
FJ
Weiler
Hartmut
H
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D018805:Sepsis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000925:Anticoagulants; D011486:Protein C