Anti-Viral and Anti-Inflammatory Mechanisms of the Innate Immune Transcription Factor Interferon Regulatory Factor 3: Relevance to Human CNS Diseases

Abstract

Interferon regulatory factor 3 (IRF3) is a transcription factor critical in the induction of antiviral immunity. IRF3 is activated following stimulation of cell membrane or cytosolic nucleic acid sensors and is essential in the induction of the IFNβ gene. Most cells constitutively express IRF3 in vitro, but little is known about the regulation of expression of IRF3 in vivo. Immunohistochemical analysis of selected human and mouse tissues demonstrated that IRF3 expression is highly organ- and cell-type specific, showing high expression in certain epithelial cells. In the CNS, while ependymal cells are strongly positive, brain parenchyma has little detectable IRF3 immunoreactivity. The importance of IRF3 in antiviral immunity has been demonstrated by the requirement for IRF3 in suppressing viral replication, but also by the demonstration that virus degrades IRF3 protein in infected cells. Furthermore, HIV-infected microglia in human CNS show abnormal IRF3+ aggregates, indicative of aberrant protein processing in vivo. In addition to antiviral immunity, IRF3 also plays a critical role in the modulation of neuroinflammation. A combination of dominant-negative and over-expression strategies in vitro as well as transgenic expression of IRF3 in vivo demonstrated that IRF3 plays a major role in modulating glial cytokine expression, i.e., suppression of proinflammatory cytokines and promotion of anti-inflammatory or immunoregulatory cytokines. These observations together suggest that IRF3 is a crucial regulator of immune responses against pathogen- and damage-associated molecules. We review recent literature on the molecular pathways of IRF3 activation and function of IRF3 and discuss their implications for CNS diseases.

IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury

“…CXCL11 was chosen as a marker of successful delivery because it has been reported to be prominently induced by IFNβ48. IRF3 is a key transcriptional regulator of the IFNα and β genes, as well as a direct activator of many IFN-stimulated genes involved in establishing an antiviral state49. CCL4 played a crucial role in protection by IFNβ against gp120 neurotoxicity in vitro .…”

Controversial Role of Toll-like Receptor 4 in Adult Stem Cells

“…We and others showed that TNF-α and subsequent NF-κB activation lead to increased proliferation of SVZ NSCs [85][86][87][88] without affecting their neuronal and glial differentiation. Contrarily to NF-κB, in the central nervous system IRF3 is believed to play a mainly antiinflammatory role (reviewed in [89]). In NSCs cultures, IRF3-target gene IFN-β inhibits the proliferation [90].…”

HIV life cycle, innate immunity and autophagy in the central nervous system

“…Tarassishin et al (41) recently demonstrated that MNGCs in the brain that were highly associated with IRF3 induction. Another group, Hornik et al (42) demonstrated in a microglia cell line that multinucleation could be triggered by TLR ligands, IFNβ, and proteins associated with Parkinson’s disease alpha-synuclein) and Alzheimer’s disease ((amyloid-beta).…”