Neutrophil extracellular traps activate STING signaling to promote dendritic cell-driven rejection after liver transplantation.

PURPOSE: Post-transplant immune rejection affects graft function. Interaction between neutrophil extracellular traps (NETs) with specific immune cells and the specific mechanism in liver transplantation were still unclear.

METHOD: Clinical patients RNA-Seq results were used for GSEA and KEGG analysis. C57BL/6 and C3H mouse models and clinical samples were use to describe the disease phenotype characteristics through multiple immunofluorescence, flow cytometry and etc. Cell co-culture experiments were performed to clarify the mechanism pathway process.

RESULTS

RNA-Seq results analysis indicated that the NETs formation pathway was upregulated. Animal models confirmed that in liver transplant immune rejection status the formation of NETs in situ and peripheral cells increased and the level of cell-free DNA (cf-DNA) in peripheral cells increased. Reactive oxygen species (ROS) as a predisposing factor for NETs accumulated more in immune rejection status and NETs are rich in mitochondrial DNA (mtDNA). NETs promote dendritic cell maturation through STING-related pathways. NETs formation increases in patients with liver transplant immune rejection and is positively correlated with disease severity.

CONCLUSION

We found that NETs can regulate dendritic cell maturation through STING-related pathways after liver transplantation, which may ultimately promote the occurrence of liver transplant rejection, providing a new perspective for clinical diagnosis, treatment and prevention of liver transplant rejection.