New players in the sepsis-protective activated protein C pathway

Abstract

Recombinant activated protein C (aPC) improves the survival of patients with severe sepsis, but the precise molecular and cellular targets through which it mediates this effect remain incompletely understood. In this issue of the JCI, Kerschen et al. show that endothelial cell protein C receptor (EPCR) is specifically expressed by mouse CD8+ dendritic cells and that these coordinators of host responses to systemic infection are required for aPC to provide protection against the lethality of sepsis. An additional study, by Cao and colleagues, recently published in the JCI, implicates the leukocyte integrin CD11b in the pathways by which aPC mediates antiinflammatory effects in the context of lethal sepsis in mice, suggesting a common thread of synergistic control of innate immune responses by life-saving aPC therapy.

Figure 1. Targets for aPC that elicit its therapeutic effects in severe sepsis.

The schematic illustrates newly identified targets for aPC in the innate immune system. Therapeutic aPC regulates neutrophil migration and extravasation by direct engagement of β₁ and β₃ integrins (12), suppresses macrophage activation dependent on integrin CD11b/CD18 (11), controls maturation and activation of CD8⁺ DCs dependent on EPCR (11), and neutralizes late-stage inflammatory mediators by degrading nuclear histones from apoptotic cells (17).