Interferons in the central nervous system: A few instruments play many tunes

Abstract

Interferons (IFNs) are implicated as an important component of the innate immune system influencing viral infections, inflammation, and immune surveillance. We review here the complex biological activity of IFNs in the central nervous system (CNS) and associated glial–immune interactions, with focus specifically on the Type I IFNs in physiological and pathological conditions. IFN-α and IFN-β are the predominant Type I IFNs in the CNS. They are produced in the CNS by glial cells, mostly microglia and astrocytes, as well as by neurons. A variety of mechanisms stimulate IFN production in glial cells, including innate stimuli from Toll-like and other receptors, which can recognize endogenous entities, as well as pathogens. We will review evidence that differential signaling by IFN-α versus IFN-β through the common heterodimeric receptor IFNAR is the basis for CNS-selective Type I IFN response, and the capacity of CNS glial cells to produce and respond to Type I IFN. Differential signaling outcomes of IFN-α and IFN-β, which have been ascribed to differential affinity for IFNAR1 and IFNAR2, determine whether Type I IFN exert pathogenic or protective roles in the CNS. These points will be discussed with reference to selected neurological diseases, and effects of Type I IFN on the integrity of the blood–brain barrier.

Neuroimmune Response in Ischemic Preconditioning

“…Most abundantly expressed by microglia is TLR4, and both endogenous and exogenous TLR4 agonists potently activate classical proinflammatory responses in microglia [18,83]. Although microglial activation has typically been considered a proinflammatory process, recent publications suggest that microglia could play a protective role in stroke [17,18,84,85] through multiple mechanisms such as metabolic and physiological support of neurons [86], production of trophic factors [85], phagocytosis of damaged cells and debris and repair of lesioned tissue by releasing matrix metalloproteinases (MMPs) [87]. While some of these responses, particularly the release of MMPs, can disrupt the BBB and be deleterious, microglia are also capable of regulating these processes and downmodulating the inflammatory response to a stimulus.…”

Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

“…Interferon (IFN)-β and IFN-α constitute the Type I IFN family, members of which play a central role in antiviral immune responses and in regulation of inflammation [3, 30]. They signal through a common receptor (IFNAR) to activate transcription of several genes including interferon regulatory factor 7 (IRF7) and IRF9, which are also involved in the induction of Type I IFN [14, 30].…”

“…They signal through a common receptor (IFNAR) to activate transcription of several genes including interferon regulatory factor 7 (IRF7) and IRF9, which are also involved in the induction of Type I IFN [14, 30]. Importantly, IFN-β is used as a first-line treatment for multiple sclerosis (MS).…”

Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain

“…Thus, brain-resident cells must produce substantial amounts of IFN after virus infection. It appears that all brain cells are capable of producing IFN, although to greatly differing extents (6,7). Most experimental attempts to identify IFN-producing cells in the brain have been in vitro approaches, and only a few of those studies have given insights into the in vivo situation.…”