Type I interferons (IFNs), IFN-α and IFN-β, represent the major effector 
cytokines of the host immune response against viruses and other intracellular 
pathogens. These cytokines are produced via activation of numerous pattern 
recognition receptors, including the Toll-like receptor signaling network, 
retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated 
protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the 
contribution of type I IFNs to peripheral immunity is well documented, they can 
also be produced by almost every cell in the central nervous system (CNS). 
Furthermore, IFNs can reach the CNS from the periphery to modulate the function 
of not only microglia and astrocytes, but also neurons and oligodendrocytes, 
with major consequences for cognition and behavior. Given the pleiotropic nature 
of type I IFNs, it is critical to determine their exact cellular impact. 
Inappropriate upregulation of type I IFN signaling and interferon-stimulated 
gene expression have been linked to several CNS diseases termed 
"interferonopathies" including Aicardi-Goutieres syndrome and ubiquitin specific 
peptidase 18 (USP18)-deficiency. In contrast, in the CNS of mice with 
virus-induced neuroinflammation, type I IFNs can limit production of other 
cytokines to prevent potential damage associated with chronic cytokine 
expression. This capacity of type I IFNs could also explain the therapeutic 
benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as 
multiple sclerosis. In this review we will highlight the importance of a 
well-balanced level of type I IFNs for healthy brain physiology, and to what 
extent dysregulation of this cytokine system can result in brain 
'interferonopathies'.