Cytoplasmic DNA sensors and their regulators

Deoxyribonucleic acid (DNA) is naturally contained within the mitochondria and nucleus of cells. DNA localized outside of these areas is generally considered to constitute damage-associated molecular patterns (DAMP) that trigger innate immune responses. The variety of these immune-stimulatory nucleic acids, coupled with the variety of proteins known to interact with DNA DAMPS and to act as sensors or regulators, is an important layer of regulation that defines the nature and breadth of inflammatory responses within a given cell or tissue. In this review, we describe the various DNA substrates that co-exist in cells, how they are sensed, and what regulates their cytoplasmic availability and recognition. We subsequently discuss how this complexity may dictate tissue-specific immune response and suggest that a more integrated view of the interconnection between pathways is necessary in order to define molecular targets for treatment intervention in inflammatory pathologies.