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

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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.

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Abbreviations

Ad-IRF3:

Adenovirus-IRF3

AIM2:

Absent in melanoma 2

ASC:

Apoptosis-associated speck-like protein containing CARD

CXCL1:

CXC chemokine ligand 1 aka GROα

CXCL10:

CXC chemokine ligand 10 aka IP-10

DAMPs:

Damage-associated molecular patterns

DAI:

DNA-dependent activator of IRFs

DN-IRF3:

Dominant negative IRF3

FFPE:

Formalin-fixed paraffin-embedded

GFAP:

Glial fibrillary acidic protein

GFP:

Green fluorescence protein

i.c.:

Intracerebral

IFI16:

Interferon-inducible protein 16

IFIT1:

Interferon-induced protein with tetratricopeptide repeats 1

IFNλ:

Interferon lambda (type III interferon)

IKKi:

IκBα kinase inducible aka IKKε

IL-1:

Interleukin 1

IL-1R:

IL-1 receptor

IL-1ra:

IL-1 receptor antagonist

iNOS:

Inducible nitric oxide synthase

IPS-1:

Interferon promoter stimulator-1

IRF3:

Interferon regulatory factor 3

MyD88:

Myeloid differentiation primary response gene 88

ISGs:

IFN-stimulated genes

ISRE:

IFN-stimulated response element

LPS:

Lipopolysaccharide

M1:

Macrophages classical activation phenotype

M2:

Macrophage alternative activation phenotype

MDA-5:

Melanoma differentiation-associated gene 5

MGC:

Multinucleated giant cell

NOD:

Nuclear oligomerization domain

NLR:

NOD-like receptor

NLRP3:

Nucleotide-binding domain and leucine-rich repeat-containing 3 aka NALP3

PAMPs:

Pathogen-associated molecular patterns

PBDA:

Porphobilinogen deaminase

PBS:

Phosphate saline buffer

PRR:

Pattern recognition receptor

PTEN:

Phosphatase and tensin homologue

Q-PCR:

Real-time reverse transcription PCR

RIG-I:

Retinoic acid-induced gene I

RLR:

RIG-I-like receptor

SOCS1:

Suppressor of cytokine signaling 1

STING:

Stimulator of interferon gene

TBK1:

TANK-binding kinase 1

TLR:

Toll-like receptors

TNFα:

Tumor necrosis factor α

TRAF:

Tumor necrosis factor receptor-associated factor

TREX 1:

Three prime repair exonuclease 1

TRIF:

TIR domain-containing adaptor inducing IFNβ

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Acknowledgement

The authors thank current and former colleagues at Einstein, Drs Brad Poulos, Ken Chen, Meng-Liang Zhao, Melissa Cosenza-Nashat, Namjong Choi, Mark Rivieccio, Olivier Loudig, Bridget Shafit-Zagardo, Laura Santambrogio and Celia F. Brosnan for their intellectual and technical contributions. The authors are especially grateful to Dr John Hiscott at McGill University, Montreal CA, who has provided plasmids and helpful discussions over the years. Dr Susan Morgello, Director of the Manhattan HIV Brain Bank (NNTC), also provided some of the brain sections used in this study. This study was supported by NIH RO1 MH55477, T32 NS007098, NIH KO1 MH084705, and P30 AI051519.

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The authors declare no competing interests.

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  1. Department of Pathology, Forchheimer 726, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Leonid Tarassishin, Avital Bauman, Hyeon-Sook Suh & Sunhee C. Lee

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  1. Leonid Tarassishin
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  2. Avital Bauman
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Correspondence to Leonid Tarassishin or Sunhee C. Lee.

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Tarassishin, L., Bauman, A., Suh, HS. et al. Anti-Viral and Anti-Inflammatory Mechanisms of the Innate Immune Transcription Factor Interferon Regulatory Factor 3: Relevance to Human CNS Diseases. J Neuroimmune Pharmacol 8, 132–144 (2013). https://doi.org/10.1007/s11481-012-9360-5

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