COMPARISON OF THE PROCOAGULANT AND IMMUNOMODULATORY PROPERTIES OF NUCLEAR, MITOCHONDRIAL, AND BACTERIAL DNA WITH RELEVANCE TO SEPSIS

Abstract

Objective – Sepsis is a syndrome in which infection triggers a systemic inflammatory and procoagulant response. Cell-free DNA (CFDNA) is elevated in sepsis, and correlates with mortality. This DNA may come from nuclear, mitochondrial, or bacterial sources. CpG motifs on bacterial and mitochondrial DNA can stimulate inflammatory responses via TLR9. CFDNA can activate coagulation via the contact pathway. CFDNA may thus play an important pathogenic role in sepsis. This study elucidates the relative effects of nuclear, mitochondrial, and bacterial DNA on inflammatory and pro-coagulant pathways with relevance to sepsis. Results – Mitochondrial DNA as well as nuclear DNA are elevated in plasma from septic patients compared to healthy controls. Bacterial, but not mitochondrial or nuclear, DNA increased neutrophil IL-6 secretion. Both mitochondrial and bacterial DNA increased neutrophil viability. Nuclear, mitochondrial, and bacterial DNA increased thrombin generation in both platelet-poor plasma and platelet-rich plasma to a similar degree. This effect was reduced by addition of corn-trypsin inhibitor and in FXII-depleted plasma, and abolished in FXI-depleted plasma, indicating dependence on the intrinsic pathway of coagulation. Independently of coagulation, DNA from all three sources was capable of causing activation of platelet integrin αIIbβ3. Conclusions – CFDNA from nuclear, mitochondrial, and bacterial sources have varying pro-inflammatory effects, although all three have similar pro-coagulant potential. The pathophysiological effects of CFDNA in sepsis may vary with the source of DNA.