The origin and properties of extracellular DNA: From PAMP to DAMP

DNA is a polymeric macromolecule whose biological activities depend on location as well as binding to associated molecules. Inside the cell, DNA is the source of genetic information and binds histones to form nucleosomes. DNA can exit the cell, however, to enter the extracellular space primarily during cell death, either apoptosis or necrosis, as well as NETosis. While bacterial DNA is a potent immune stimulant by virtue of its CpG motifs, mammalian DNA, which is ordinarily inactive, can acquire activity by associating with nuclear, cytoplasmic and serum proteins which promote its uptake into cells to stimulate internal DNA sensors, including Toll-like receptor 9. Among these proteins, anti-DNA autoantibodies can form immune complexes with DNA to stimulate plasmacytoid dendritic cells to produce type 1 interferon. Together, these findings suggest that the immune properties of DNA are mutable and diverse, reflecting its context and the array of attached molecules.

► Extracellular DNA can emanate from cells during apoptosis, necrosis and NETosis. ► DNA's immune activity depends on molecules that promote access to internal sensors. ► Anti-DNA form immune complexes that stimulate plasmacytoid dendritic cells. ► DNA can interact with HMGB1, a non-histone nuclear protein with alarmin activity.