The role of nuclear macromolecules in innate immunity.

Nuclear macromolecules, in addition to their intracellular role in regulating cell function, can translocate into the extracellular space where they can activate innate immunity. This translocation can occur in various settings and reflects the dynamic nature of nuclear structure. Of nuclear molecules, DNA and the DNA-binding protein, HMGB1, display distinct patterns of immune activity. For DNA, immune activity depends on sequence, base methylation, and context. While bacterial DNA is an immune activator, mammalian DNA is either inert or inhibitory when free. In contrast, mammalian DNA in the form of immune complexes can trigger immune cell activation. As shown in in vivo and in vitro studies, DNA can exit cells during apoptotic as well as necrotic cell death in a process that may depend on the presence of macrophages. Like DNA, HMGB1 can exit cells and acquire immune properties. For HMGB1, the translocation occurs in macrophages that have been stimulated by Toll-like receptor (TLR) ligands as well as cytokines; HMGB1 release can also occur with apoptotic as well as necrotic death. While HMGB1 alone can display cytokine activity, it may also activate cells in conjunction with other immune stimulators such as TLR ligands. For both DNA and HMGB1, the immune properties may therefore reflect the array of other endogenous as well as exogenous molecules present.