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

Abstract

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.

Figure 1

The generation of extracellular DNA during apoptosis. The figure illustrates the various mechanism by which DNA can leave cells during apoptosis and form immune complexes with anti-DNA antibodies. During apoptosis, the nucleus fragments and condenses and some DNA migrates to the surface to enter blebs (small dark circles on the cell surface). During late apoptosis or secondary necrosis, DNA exits the dying cell in various forms. Thus, DNA may leave cells alone or in association with HMGB1. Even if DNA and HMGB1 leave the cell separately, they may associate in the extracellular space. DNA may also leave cells in the form of microparticles (the detached form of blebs) with DNA present either on the particle surface or accessible in the particle interior to antibodies because of particle permeability. The various sources of DNA can all form immune complexes with anti-DNA autoantibodies, although the size and resulting composition of the complexes will all differ, ranging from a simple complex of DNA and anti-DNA to large, multicomponent complexes assembled on a particle structure. Some aspects of this figure, while plausible, have not yet been experimentally verified.