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

Edward Kerschen ¹, Irene Hernandez , Mark Zogg

⁰Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin 53226, USA.

The Journal of Clinical Investigation +

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August 18, 2010

View abstract on PubMed

Summary

Activated protein C (aPC) therapy requires specific cell receptors on immune cells to reduce sepsis mortality. Dendritic cells expressing EPCR are critical targets for this life-saving treatment.

Area Of Science

Immunology
Hematology
Pharmacology

Background

Activated protein C (aPC) therapy is effective in severe sepsis.
aPC's mortality reduction relies on cell signaling via protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR).
Candidate targets include vascular endothelial cells and leukocytes.

Purpose Of The Study

To investigate the role of EPCR and PAR1 on hematopoietic cells in aPC therapy.
To identify specific immune cell populations targeted by aPC.
To explore EPCR-independent effects of aPC.

Main Methods

Utilized mouse models of endotoxemia and sepsis.
Employed a cell-signaling variant of aPC (5A-aPC).
Conducted adoptive transfer experiments with dendritic cells from wild-type and EPCR-deficient mice.

Main Results

Hematopoietic cell expression of EPCR and PAR1 is essential for 5A-aPC efficacy in endotoxemia.
EPCR expression on murine immune cells is primarily found on CD8+ conventional dendritic cells.
Adoptive transfer of EPCR-expressing dendritic cells restored aPC's therapeutic effect in EPCR-deficient mice.
5A-aPC demonstrated EPCR-independent anti-inflammatory effects on dendritic cells and suppressed IFN-gamma production.

Conclusions

EPCR and PAR1 on hematopoietic cells are crucial for aPC therapy.
EPCR-expressing dendritic cells are a key target for aPC.
aPC exhibits EPCR-independent anti-inflammatory actions on innate immune cells, suggesting broader therapeutic mechanisms.

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