Functional Characterization of Murine Interferon Regulatory Factor 5 (IRF-5) and Its Role in the Innate Antiviral Response

Paun, Andrea; Reinert, Thomas; Jiang, Zhaozhao; Medin, Carey L.; Balkhi, Mumtaz Yaseen; Fitzgerald, Katherine A.; Pitha, Paula M.

doi:10.1074/jbc.m800501200

Cited by 119 publications

(136 citation statements)

References 62 publications

(106 reference statements)

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“…Unexpectedly, the control ODN consisting of CCT repeats also to the neutrophils, local keratinocytes and fibroblasts in the burned skin could also contribute to the rapid systemic inflammation by producing inflammatory cytokines. The keratinocytes and fibroblasts were identified as TLR9 and IRF5 expressing cells (36)(37)(38), and therefore could be activated by the mtDNA released from burned skin through the TLR9-MyD88-NF-κB/IRF5 pathways. As shown in Figure 3, IRF5 expression was accompanied by increased expression of TLR9, MyD88 and NF-κB in the burned skin.…”

Section: Discussionmentioning

confidence: 99%

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

Xiao

et al. 2017

Mol Med

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Previously, we showed that an oligodeoxynucleotide (ODN) with AAAG repeats (AAAG ODN) rescued mice from fatal acute lung injury (ALI) induced by influenza virus and inhibited production of tumor necrosis factor-α (TNF-α) in the injured lungs. However, its underlying mechanisms remain to be elucidated. Upon the bioinformatic analysis revealing that the sequence of AAAG ODN is in consensus with the interferon regulatory factor 5 (IRF5) binding site in the cis-regulatory elements of proinflammatory cytokines, we tried to explore whether AAAG ODN could attenuate burn injury-induced systemic inflammatory responses by inhibiting the IRF5 pathway. Using a mouse model with sterile systemic inflammation induced by burn injury, we found that AAAG ODN prolonged the lifespan of the mice, decreased the expression of IRF5 in the injured skin, reduced the production of TNF-α and IL-6 in the blood and injured skin, and attenuated the ALI. These effects were correlated with AAAG ODN-mediated inhibition of nuclear translocation of IRF5. The data suggest that AAAG ODN could act as a cytoplasmic decoy capable of interfering the function of IRF5 and be developed as a drug candidate for the treatment of inflammatory diseases. online address: http://www.molmed.org

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Section: Discussionmentioning

confidence: 99%

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

Xiao

et al. 2017

Mol Med

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“…Since IRF5 has been reported to be required for an optimal type I IFN response in vivo in the context of VSV, HSV, and NDV infections (20,21), we assessed its impact on the systemic levels of type I IFN after WNV infection (Fig. 3A).…”

Section: At Day 4 After Infection 4 Of 11 Irf5mentioning

confidence: 99%

“…Subsequent experiments suggested that IRF5 regulates type I IFN production in vivo after viral infection (20,21), and a lack of this function in Irf5 Ϫ/Ϫ mice was associated with enhanced susceptibility to infection with vesicular stomatitis virus (VSV) or herpes simplex virus (HSV). In response to Newcastle disease virus (NDV) infection, IRF5 induced overlapping and distinct sets of genes compared to IRF7, including the induction of type I IFN and proinflammatory cytokines (20,22).…”

mentioning

confidence: 99%

Interferon Regulatory Factor 5-Dependent Immune Responses in the Draining Lymph Node Protect against West Nile Virus Infection

Thackray

Shrestha

Richner

et al. 2014

J Virol

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Upon activation of Toll-like and RIG-I-like receptor signaling pathways, the transcription factor IRF5 translocates to the nucleus and induces antiviral immune programs. The recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (Dock2 mu/mu ) in several Irf5 ؊/؊ mouse colonies has complicated interpretation of immune functions previously ascribed to IRF5. To define the antiviral functions of IRF5 in vivo, we infected backcrossed Irf5 ؊/؊ ؋ Dock2 wt/wt mice (here called Irf5 ؊/؊ mice) and independently generated CMV-Cre Irf5 fl/fl mice with West Nile virus (WNV), a pathogenic neurotropic flavivirus. Compared to congenic wild-type animals, Irf5؊/؊ and CMV-Cre Irf5 fl/fl mice were more vulnerable to WNV infection, and this phenotype was associated with increased infection in peripheral organs, which resulted in higher virus titers in the central nervous system. The loss of IRF5, however, was associated with only small differences in the type I interferon response systemically and in the draining lymph node during WNV infection. Instead, lower levels of several other proinflammatory cytokines and chemokines, as well as fewer and less activated immune cells, were detected in the draining lymph node 2 days after WNV infection. WNV-specific antibody responses in Irf5 ؊/؊ mice also were blunted in the context of live or inactivated virus infection and this was associated with fewer antigen-specific memory B cells and long-lived plasma cells. Our results with Irf5 ؊/؊ mice establish a key role for IRF5 in shaping the early innate immune response in the draining lymph node, which impacts the spread of virus infection, optimal B cell immunity, and disease pathogenesis. A canonical model for type I IFN production after virus infection is a two-step positive feedback loop that is regulated by Interferon regulatory factor 3 (IRF3) and IRF7 (1). Detection of viral nucleic acids by Toll-like receptors (TLRs), RIG-I-like (RLRs) receptors, or DNA sensors induces nuclear localization of IRF3, which in concert with NF-B and ATF-2/c-Jun stimulates transcription, synthesis, and secretion of IFN-␤ by infected cells. Extracellular interferon beta (IFN-␤) binds to the type I IFN receptor (IFNAR) and triggers activation of the JAK-STAT signaling pathway and induction of IFN-stimulated genes (ISGs) (2), which inhibit viral entry, translation, replication, and assembly through a variety of independent mechanisms (reviewed in reference 3). While IRF3 is constitutively expressed in many tissues, IRF7 is an ISG required for the expression of most IFN-␣ subtypes and is thus a key mediator of the type I IFN amplification loop (1, 4).Noncanonical signaling pathways also induce type I IFN responses. Even with genetic ablation of IRF3 and IRF7 (Irf3 Ϫ/Ϫ ϫ Irf7 Ϫ/Ϫ double-knockout [DKO] cells or mice), type I IFN was produced after infection with West Nile virus (WNV), dengue virus, murine norovirus, or murine cytomegalovirus, albeit at reduced levels compared to wild-type ...

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“…16 Independent research has demonstrated that IRF5 has an important role in IFN production in a stimulation-and cell-type dependent manner. 17,18 Moreover, these authors reported that Irf5-deficient mice exhibited increased susceptibility to viral infection, as well as significant decreases in the induction of serum type I IFN and of the inflammatory cytokines interleukin-6 and tumor necrosis factor-a after viral infection. With this information in mind, in the present work we aimed at: first, replicating the effect of the two top-associated SNPs originally described 12 in three independent cohorts from Spain, in order to quantify the effect size of these polymorphisms in MS predisposition; second, characterizing whether the response of MS patients to IFN-b therapy is conditioned by those IRF5 polymorphisms and third, evaluating whether there is an association between HHV-6 infection and the IRF5 variants.…”

Section: Introductionmentioning

confidence: 99%

Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection

et al. 2010

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In recent reports, IRF5 polymorphisms showed significant association with multiple sclerosis (MS) susceptibility in three studied populations and Irf5-deficient mice exhibited an increased susceptibility to viral infection, linked to a significant decrease in the induction of serum type I interferon (IFN). In the present study, we evaluated the association of two IRF5 polymorphisms with MS predisposition and we also addressed whether these polymorphisms were associated with active replication of human herpes virus-6 (HHV-6) observed in a subgroup of MS patients, and/or with response to IFN-b therapy. A total of 1494 MS patients and 1506 ethnically matched controls were genotyped for rs4728142 and rs3807306 with TaqMan pre-designed assays. One hundred and six patients were classified as responders to IFN-b therapy (no relapses/increases in EDSS over the 2-year follow-up) and 112 as non-responders (at least two relapses or an increase in expanded disability status scale (EDSS) of at least one point during the same period). The combined analysis of available datasets yielded an effect size on MS with odds ratio (OR) MantelÀHaenszel ¼ 1.14 (Po0.002) for the IRF5 polymorphisms rs4728142 and rs3807306. Additionally, trends for association were observed between rs3807306T and infection with HHV-6 [p ¼ 0.05, OR (95% CI) ¼ 1.56 (1.00-2.44)] and response to IFN-b therapy [P ¼ 0.09, OR (95% CI) ¼ 1.39 (0.95-2.05)].

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Functional Characterization of Murine Interferon Regulatory Factor 5 (IRF-5) and Its Role in the Innate Antiviral Response

Cited by 119 publications

References 62 publications

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

Interferon Regulatory Factor 5-Dependent Immune Responses in the Draining Lymph Node Protect against West Nile Virus Infection

Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection

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