Cytosolic DNA sensors and glial responses to endogenous DNA

Genomic instability is a key driving force for the development and progression of many neurodegenerative diseases and central nervous system (CNS) cancers. The initiation of DNA damage responses is a critical step in maintaining genomic integrity and preventing such diseases. However, the absence of these responses or their inability to repair genomic or mitochondrial DNA damage resulting from insults, including ionizing radiation or oxidative stress, can lead to an accumulation of self-DNA in the cytoplasm. Resident CNS cells, such as astrocytes and microglia, are known to produce critical immune mediators following CNS infection due to the recognition of pathogen and damage-associated molecular patterns by specialized pattern recognition receptors (PRRs). Recently, multiple intracellular PRRs, including cyclic GMP-AMP synthase, interferon gamma-inducible 16, absent in melanoma 2, and Z-DNA binding protein, have been identified as cytosolic DNA sensors and to play critical roles in glial immune responses to infectious agents. Intriguingly, these nucleic acid sensors have recently been shown to recognize endogenous DNA and trigger immune responses in peripheral cell types. In the present review, we discuss the available evidence that cytosolic DNA sensors are expressed by resident CNS cells and can mediate their responses to the presence of self-DNA. Furthermore, we discuss the potential for glial DNA sensor-mediated responses to provide protection against tumorigenesis versus the initiation of potentially detrimental neuroinflammation that could initiate or foster the development of neurodegenerative disorders. Determining the mechanisms that underlie the detection of cytosolic DNA by glia and the relative role of each pathway in the context of specific CNS disorders and their stages may prove pivotal in our understanding of the pathogenesis of such conditions and might be leveraged to develop new treatment modalities.