Neutrophil extracellular trap components increase the expression of coagulation factors.

Neutrophil extracellular traps (NETs) represent an important link between inflammation and thrombosis. Here, the present study aimed to investigate the influence of the NET components, DNA and histone H4, on hemostatic gene expression. A further aim was to confirm the influence of H4 on the expression of tissue factor (TF) and investigate a potential effect of DNA, and to test the involvement of miR-17/92 and its paralog miR-106b-25 in this regulation. In HepG2 cells, the mRNA levels of factor VII and factor XII, which are crucial in the activation of the coagulation cascade, and of serpin family F member 2 (encoding α2-antiplasmin) were significantly upregulated by DNA and H4; while the mRNA levels of factor V, which is essential for thrombin generation of protein S, a cofactor of protein C that also has the ability to inhibit the factor X activation pathway, and of serpin family C member 1 (encoding antithrombin, the main endogenous anticoagulant) were significantly upregulated only by H4. H4 and DNA also provoked an increase in hepatocyte nuclear factor 4α (HNF4A) mRNA expression that could be responsible for the increase in the expression of certain coagulant factors. In THP-1 cells, it was also demonstrated that H4 caused an increase in TF mRNA while decreasing several of the microRNAs (miRNA/miRs) of the cluster miR-17/92, which may in part explain the increase in the expression of TF. The present results suggest the ability of NET components to alter the hemostatic balance and a possible involvement of HNF4α and miRNAs in this regulation.