The origin of extracellular DNA during the clearance of dead and dying cells

Abstract

DNA is a nuclear molecule that has both an intracellular and extracellular role. Inside the cell, it is the essential molecule of heredity while outside the cell it can have immunological activity, both alone and in the context of immune complexes. Furthermore, extracellular DNA has information content that can be mined by genomic techniques. Because of the association of extracellular DNA with clinical conditions marked by cell death, dead and dying cells have been considered the origin of this material. To investigate this process, in vitro and in vivo systems have been used to determine the release of DNA from cells, using Jurkat T cells as a model. Thus, in vitro, apoptotic Jurkat cells release DNA whereas necrotic cells do not. The presence of macrophages in these cultures, however, modifies the release process, causing release from necrotic cells as well. In in vivo experiments in which Jurkat cells are administered to normal mice, both apoptotic and necrotic cells give rise to DNA in the blood in a process that requires macrophages and can be modified by glucocorticoids. In this model, female and male mice differ in the extent of DNA release from the administered Jurkat cells. Together, these results indicate that, while apoptosis and necrosis can lead to a blood DNA response, this process requires macrophages and may be hormonally mediated.