Interferon Regulatory Factor 3 Inhibits Astrocyte Inflammatory Gene Expression Through Suppression of the Proinflammatory miR-155 and miR-155

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
Glia (Impact Factor: 6.03). 12/2011; 59(12):1911-22. DOI: 10.1002/glia.21233
Source: PubMed

ABSTRACT Astrocytes, together with microglia and macrophages, participate in innate inflammatory responses in the CNS. Although inflammatory mediators such as interferons generated by astrocytes may be critical in the defense of the CNS, sustained unopposed cytokine signaling could result in harmful consequences. Interferon regulatory factor 3 (IRF3) is a transcription factor required for IFNβ production and antiviral immunity. Most cells express low levels of IRF3 protein, and the transcriptional mechanism that upregulates IRF3 expression is not known. In this study, we explored the consequence of adenovirus-mediated IRF3 gene transfer (Ad-IRF3) in primary human astrocytes. We show that IRF3 transgene expression suppresses proinflammatory cytokine gene expression upon challenge with IL-1/IFNγ and alters astrocyte activation phenotype from a proinflammatory to an anti-inflammatory one, akin to an M1-M2 switch in macrophages. This was accompanied by the rescue of neurons from cytokine-induced death in glial-neuronal co-cultures. Furthermore, Ad-IRF3 suppressed the expression of microRNA-155 and its star-form partner miR-155*, immunoregulatory miRNAs highly expressed in multiple sclerosis lesions. Astrocyte miR-155/miR155* were induced by cytokines and TLR ligands with a distinct hierarchy and involved in proinflammatory cytokine gene induction by targeting suppressor of cytokine signaling 1, a negative regulator of cytokine signaling and potentially other factors. Our results demonstrate a novel proinflammatory role for miR-155/miR-155* in human astrocytes and suggest that IRF3 can suppress neuroinflammation through regulating immunomodulatory miRNA expression. © 2011 Wiley-Liss, Inc.

Download full-text


Available from: Sunhee C Lee, May 26, 2014
  • Source
    • "In addition to the contrasting responses to LPS, our study also revealed another important distinction between mouse and human astrocytes, i.e., their differential responses to IL-1. Given the robust responses of human astrocytes to IL-1 (John et al., 2003; Lee et al., 1993b; Liu et al., 1996; Tarassishin et al., 2011a), the lack of response of mouse astrocytes to IL-1 in our study (such as lack of TNFa and nitrite production) was surprising. When cytokine mixture (IL-1/ IFNc) was used, iNOS was induced in mouse astrocytes in magnitudes similar to LPS stimulation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment of cultures with toll-like receptor (TLR) ligands or cytokines has become a popular approach to investigate astrocyte neuroinflammatory responses and to simulate the neural environment in various CNS disorders. However, despite much effort, the mechanism of astrocyte activation such as their responses to the TLR ligands and IL-1 remain highly debated. We compared highly pure primary mouse and human astrocyte cultures in their ability to produce proinflammatory mediators (termed “A1”) and immunoregulatory mediators (termed “A2”) in response to LPS, poly IC, and IL-1 stimulation. In human astrocytes, IL-1 induced both A1 and A2 responses, poly IC induced mostly A2, and LPS induced neither. In mouse astrocytes, LPS induced mostly an A1-predominant response, poly IC induced both A1 and A2, and IL-1 neither. In addition, mouse astrocytes produce abundant IL-1 protein, whereas human astrocytes did not, despite robust IL-1 mRNA expression. Of the TLR4 receptor complex proteins, human astrocytes expressed TLR4 and MD2 but not CD14, whereas mouse astrocytes expressed all three. Mouse astrocyte CD14 (cell-associated and soluble) was potently upregulated by LPS. Silencing TLR4 or CD14 by siRNA suppressed LPS responses in mouse astrocytes. In vivo, astrocytes in LPS-injected mouse brains also expressed CD14. Our results show striking differences between human and mouse astrocytes in the use of TLR/IL-1R and subsequent downstream signaling and immune activation. IL-1 translational block in human astrocytes may be a built-in mechanism to prevent autocrine and paracrine cell activation and neuroinflammation. These results have important implications for translational research of human CNS diseases. GLIA 2014
    Glia 06/2014; 62(6). DOI:10.1002/glia.22657 · 6.03 Impact Factor
  • Source
    • "As transcription factors, IRFs can also directly modulate miRNA gene expression. For example, experimental over-expression of IRF-3 suppresses the expression of miR-155 and miR-155* in primary human astrocytes (Tarassishin et al., 2011). However, in additional to IFN␥R mRNA (Banerjee et al., 2010), another direct target of miR-155 is the SOCS IFN-signalling regulatory molecule. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interferons (IFNs) are cytokines that are spontaneously produced in response to virus infection. They act by binding to IFN-receptors (IFN-R), which trigger JAK/STAT cell signalling and the subsequent induction of hundreds of IFN-inducible genes, including both protein-coding and microRNA genes. IFN-induced genes then act synergistically to prevent virus replication and create an anti-viral state. miRNA are therefore integral to the innate response to virus infection and are important components of IFN-mediated biology. On the other hand viruses also encode miRNAs that in some cases interfere directly with the IFN response to infection. This review summarizes the important roles of miRNAs in virus infection acting both as IFN-stimulated anti-viral molecules and as critical regulators of IFNs and IFN-stimulated genes. It also highlights how recent knowledge in RNA editing influence miRNA control of virus infection.
    Molecular Immunology 08/2013; 56(4):781-793. DOI:10.1016/j.molimm.2013.07.009 · 3.00 Impact Factor
  • Source
    • "Previous studies have demonstrated that loss of critical components of the IFN signaling pathway, such as STAT1, can lead to enhanced inflammation and pathology during infection with HSV-1, and such disease can be independent of changes in viral titers (Lundberg et al., 2008; Pasieka et al., 2009, 2008). Several studies have also reported that IRF-3 has antiinflammatory properties which may help control immune-mediated pathology (Hua et al., 2002; Suh et al., 2009; Tarassishin et al., 2011a, 2011b). These studies therefore prompted us to investigate in this study whether a dysfunctional immune response was contributing to the observed pathology and mortality. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interferon regulatory factors IRF-3 and IRF-7 are central to the establishment of the innate antiviral response. This study examines HSV-1 pathogenesis in IRF-3(-/-), IRF-7(-/-) and double-deleted IRF3/7(-/-) (DKO) mice. Bioluminescence imaging of infection revealed that DKO mice developed visceral infection following corneal inoculation, along with increased viral burdens in all tissues relative to single knockout mice. While all DKO mice synchronously reached endpoint criteria 5 days post infection, the IRF-7(-/-) mice survived longer, indicating that although IRF-7 is dominant, IRF-3 also plays a role in controlling disease. Higher levels of systemic pro-inflammatory cytokines were found in IRF7(-/-) and DKO mice relative to wild-type and IRF-3(-/-) mice, and IL-6 and G-CSF, indicative of sepsis, were increased in the DKO mice relative to wild-type or single-knockout mice. In addition to controlling viral replication, IRF-3 and -7 therefore play coordinating roles in modulation of inflammation during HSV infection.
    Virology 06/2013; 444(1-2). DOI:10.1016/j.virol.2013.05.034 · 3.28 Impact Factor
Show more