Phenotype-Haplotype Correlation of IRF5 in Systemic Sclerosis: Role of 2 Haplotypes in Disease Severity
Philippe DieudéK. DawidowiczMickaël GuedjYona LegrainJ. WipffΈ. HachullaÉlisabeth DiotJean SibiliaLuc MouthonJ. CabanéZahir AmouraJEAN-LUC CRAKOWSKIP. CarpentierJérôme AvouacOlivier MeyerAndré KahanCathérine BoileauYannick Allanore
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Objective. Identification of an association between IRF5 rs2004640 and systemic sclerosis (SSc) has highlighted a key role for type 1 interferon (IFN). Additional functional IRF5 variants have been identified as autoimmune susceptibility factors. Our aim was to investigate whether IRF5 haplotypes confer susceptibility to SSc, and to perform genotype haplotype-phenotype correlation analyses. Methods. We genotyped IRF5 rs377385, rs2004640, and rs10954213 in 1623 individuals of French European Caucasian origin. SSc patient subphenotypes were analyzed according to cutaneous subsets and for SSc-related pulmonary fibrosis. Results. Case-control studies of single markers revealed an association between IRF5 rs3757385, rs2004640, and rs10954213 variants and SSc. We identified an IRF5 risk haplotype “R” (p adj = 0.024, OR 1.23, 95% CI 1.07–1.40) and a mirrored protective haplotype “P” (p adj = 8.8 × 10 −3 , OR 0.78, 95% CI 0.68–0.90) for SSc susceptibility. Genotype-phenotype correlation analyses failed to detect any association with a single marker. By contrast, phenotype-haplotype correlation analysis was able to detect intra-cohort association and to discriminate SSc patients with from those without the following clinical traits: “R” and/or “P” haplotypes identified diffuse cutaneous SSc (p = 0.0081) and fibrosing alveolitis (p = 0.018). Conclusion. IRF5 haplotypes are more informative than single markers, suggesting that they could be helpful for risk stratification of SSc patients. Our study provides further evidence of a key role of IRF5 in SSc severity.Keywords:
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Interferon Regulatory Factor 5 (IRF5) plays a major role in setting up an inflammatory macrophage phenotype, but the molecular basis of its transcriptional activity is not fully understood. In this study, we conduct a comprehensive genome-wide analysis of IRF5 recruitment in macrophages stimulated with bacterial lipopolysaccharide and discover that IRF5 binds to regulatory elements of highly transcribed genes. Analysis of protein:DNA microarrays demonstrates that IRF5 recognizes the canonical IRF-binding (interferon-stimulated response element [ISRE]) motif in vitro. However, IRF5 binding in vivo appears to rely on its interactions with other proteins. IRF5 binds to a noncanonical composite PU.1:ISRE motif, and its recruitment is aided by RelA. Global gene expression analysis in macrophages deficient in IRF5 and RelA highlights the direct role of the RelA:IRF5 cistrome in regulation of a subset of key inflammatory genes. We map the RelA:IRF5 interaction domain and suggest that interfering with it would offer selective targeting of macrophage inflammatory activities.
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Interferon regulatory factor(IRF)members are composed of 10 different proteins, including IRF1 ~ IRF9 and viruses IRF(V-IRF). These IRFs regulate the transcription of type I IFN genes as transcription factors.Systemic lupus erythematosus(SLE)is an autoimmune disease characterized by a large number of autoantibodies and precipitated immune complexes, which can cause the damage of multiple organs and systems.Type I interferon system, especially the IFN-α is an important pathogenic factor in the process of SLE morbidity.SLE patients may have high level of IFN-α, which could affect the activation of the immune system to promote the development of SLE through the regulation of a variety of immune cells′ activation, differentiation and function.Besides IRF3 and IRF7, the transcription factor IRF5 gene has also been shown to be related to the production of type I interferon and is an important regulator of the IFN pathway, and its genetic polymorphism and expression abnormality lead to the susceptibility of SLE.In addition to regulating the expression of type I IFN genes, IRF5 is also associated with other signaling pathways, including B cell transformation of IgG, macrophage polarization and apoptosis, and these signaling pathways in the pathogenesis of SLE also play a very important role.This article reviews the role of IRF5 in the development of SLE disease.
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SLE; IRF5; Signal pathways
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Abstract Interferon Regulatory Factor 5 (IRF5) is a member of the IRF family of proteins which predominately serve as immune regulators in response to extracellular pathogens. IRF5 has also been characterized as a tumor suppressor gene where loss of its expression has been observed in a variety of tumor types including blood cancers, breast and colon cancer. In cell types that constitutively express IRF5, such as immune and epithelial cells, it generally resides in the cytoplasm. Once activated by a stimulus that induces post-translational modification(s) of IRF5, it undergoes dimerization and translocation to the nucleus. In the nucleus, IRF5 acts as a transcription factor binding to specific DNA sequences in the promoter regions of target genes known as interferon-sensitive response elements (ISRE) or interferon regulatory elements (IRE). Upon binding to these elements, IRF5 can positively regulate transcription of its target genes, such as pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-12, and interferon (IFN)-α, or negatively regulate targets such as IL-10. Most of our current understanding of IRF5 expression and function comes from examining its role in the immune system. Recent data from our lab has shown that IRF5 is a new tumor suppressor gene in breast cancer that controls metastasis in part by regulating expression of the chemokine receptor CXCR4. We detected a graded decrease in IRF5 expression that correlated with advanced disease stage in patients with ductal carcinoma in situ (DCIS), and almost complete loss of IRF5 expression in nearly all of the breast tissues examined from patients diagnosed with invasive ductal carcinoma (IDC). IRF5 expression was easily detectable in mammary epithelial cells from healthy donors and patients with atypical ductal hyperplasia (ADH). Interestingly, in these same tumor specimens from IDC patients, we noticed that a large percentage of infiltrating immune cells expressed high levels of IRF5. Together, these findings suggest at least two distinct functions for IRF5 in the breast tumor microenvironment: 1) in the tumor cell itself and 2) in the infiltrating immune cells of IDC patients. We hypothesize that it is the initial loss of IRF5 expression in mammary epithelial cells of patients with DCIS that reprograms the tumor microenvironment to allow for tumor progression and metastasis. To begin to understand why loss of IRF5 in breast tumor cells allows for disease progression, we worked primarily in an in vitro 3D culture model of a highly invasive human breast cancer cell line, MDA-MB-231, which does not express detectable levels of IRF5. A population of MDA-MB-231 cells were retrovirally infected with either an empty vector or IRF5 pBabe plasmid (EV-231 or IRF5-231) and were used to assess cell proliferation, migration, invasion, chemotaxis, and gene expression profiles. In particular, a focused tumor cytokine array was performed to measure differences in chemokine and chemokine receptor expression between EV-231 and IRF5-231 cells grown in 3D culture. Co-culture of these cells with immune cell types allowed for characterization of an immune response. This work demonstrates that loss of IRF5 in breast cancer cell lines allows for increased tumor cell migration/invasion and significantly alters the expression of several genes important in the regulation of immune cell trafficking and activation. The data supports an otherwise unknown role for IRF5 as an immune regulator in epithelial cells. The ability of IRF5 to slow mammary cell growth and metastasis, as well as shape the tumor-immune microenvironment, points to the importance of studying this new gene regulator in mammary epithelial cells. Citation Format: Erica M. Pimenta, Betsy J. Barnes. Regulation of the breast tumor microenvironment by interferon regulatory factor 5 (IRF5). [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A79.
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Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.
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Interferon regulatory factor 5 (IRF5) has been described as an important factor in regulating inflammatory response and a key transcription factor in the immune system. In antiviral response, IRF5 promotes the expression of type 1 interferon (IFN) and is also important in the differentiation of macrophages towards pro-inflammatory phenotypes, regulating B-cell maturity and antibody production. Some cancer patients treated with IFNα manifest symptoms resembling systemic lupus erythematosus (SLE). An important mechanism in this response is IRF5 that triggers apoptosis. Herein, we discuss the functional importance of IRF5 in rheumatoid arthritis (RA) and SLE in a setting of polymorphic mutations at the human Irf5 locus. This paper describes murine models, the lessons of IRF functionality learned from these models and the consequences of autoimmune diseases. It is hypothesized that modulation of IRF5 activity may be beneficial in autoimmune diseases therapies.
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IRF5 is a member of the Interferon Regulatory Factor (IRF) family of transcription factors activated downstream of the Toll-Like receptors (TLRs). Polymorphisms in IRF5 have been shown to be associated with the autoimmune disease Systemic Lupus Erythematosus (SLE) and other autoimmune conditions, suggesting a central role for IRF5 in the regulation of the immune response. Four different IRF5 isoforms originate due to alternative splicing and to the presence or absence of a 30 nucleotide insertion in IRF5 exon 6. Since the polymorphic region disturbs a PEST domain, a region associated with protein degradation, we hypothesized that the isoforms bearing the insertion might have increased stability, thus explaining the association of individual IRF5 isoforms with SLE. As the E3 ubiquitin ligase TRIpartite Motif 21 (TRIM21) has been shown to regulate the stability and hence activity of members of the IRF family, we investigated whether IRF5 is subjected to regulation by TRIM21 and whether dysregulation of this mechanism could explain the association of IRF5 with SLE. Our results show that IRF5 is degraded following TLR7 activation and that TRIM21 is involved in this process. Comparison of the individual IRF5 variants demonstrates that isoforms generated by alternative splicing are resistant to TRIM21-mediated degradation following TLR7 stimulation, thus providing a functional link between isoforms expression and stability/activity which contributes to explain the association of IRF5 with SLE.
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