37 results on '"Udalova, Irina A."'
Search Results
2. Advances and challenges in targeting IRF5, a key regulator of inflammation.
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Almuttaqi, Hannah and Udalova, Irina A.
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INTERFERON regulatory factors , *INFLAMMATORY bowel diseases , *SYSTEMIC lupus erythematosus , *TRANSCRIPTION factors , *AUTOIMMUNE diseases , *TYPE I interferons - Abstract
Interferon regulatory factor 5 (IRF5) belongs to a family of transcription factors, originally implicated in antiviral responses and interferon production. However, studies conducted in different laboratories over the last decade have placed IRF5 as a central regulator of the inflammatory response. It has become clear that IRF5 contributes to the pathogenesis of many inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus. Given the role of IRF5 in physiology and disease, IRF5 represents a potential therapeutic target. However, despite a significant interest from the pharmaceutical industry, inhibitors that interfere with the IRF5 pathway remain elusive. Here, we review the advances made by various studies in targeting multiple steps of signalling leading to IRF5 activation with their therapeutic potential, and the possible complications of such strategies are discussed. [ABSTRACT FROM AUTHOR]
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- 2019
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3. Diverse mechanisms of IRF5 action in inflammatory responses.
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Khoyratty, Tariq E. and Udalova, Irina A.
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INTERFERON regulatory factors , *MYELOID metaplasia , *GRANULOCYTES , *MACROPHAGES , *PHENOTYPES , *CHROMATIN - Abstract
Interferon regulatory factor 5 (IRF5) is a key signal-dependent transcription factor in myeloid cells. Its expression is induced by granulocyte-macrophage colony stimulating factor and interferon-gamma. IRF5 protein is further activated in response to stimulation, translocating to the nucleus where it mediates inflammatory responses. IRF5 is capable of both the up-regulation of pro-inflammatory genes and repressing anti-inflammatory mediators, thus polarising macrophages to a pro-inflammatory phenotype. We discuss IRF5 interactions with a wide range of transcriptional regulators that give rise to its diverse effects at the level of chromatin. [ABSTRACT FROM AUTHOR]
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- 2018
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4. Macrophage heterogeneity in the context of rheumatoid arthritis.
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Udalova, Irina A., Mantovani, Alberto, and Feldmann, Marc
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MACROPHAGES , *RHEUMATOID arthritis , *SYNOVIAL membranes , *PHENOTYPES , *CELLULAR signal transduction , *ANIMALS , *CELL differentiation , *DRUG therapy , *DRUG design , *GENES , *HEMATOPOIESIS , *MONOCYTES , *PROTEINS , *PHYSIOLOGY - Abstract
Macrophages are very important in the pathogenesis of rheumatoid arthritis (RA). The increase in the number of sublining macrophages in the synovium is an early hallmark of active rheumatic disease, and high numbers of macrophages are a prominent feature of inflammatory lesions. The degree of synovial macrophage infiltration correlates with the degree of joint erosion, and depletion of these macrophages from inflamed tissue has a profound therapeutic benefit. Research has now uncovered an unexpectedly high level of heterogeneity in macrophage origin and function, and has emphasized the role of environmental factors in their functional specialization. Although the heterogeneous populations of macrophages in RA have not been fully characterized, preliminary results in mouse models of arthritis have contributed to our understanding of the phenotype and ontogeny of synovial macrophages, and to deciphering the properties of monocyte-derived infiltrating and tissue-resident macrophages. Elucidating the molecular mechanisms that drive polarization of macrophages towards proinflammatory or anti-inflammatory phenotypes could lead to identification of signalling pathways that inform future therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2016
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5. Quantitative prediction of NF-KB DNA- protein interactions.
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Udalova, Irina A., Mott, Richard, Field, Dawn, and Kwiatkowski, Dominic
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NUCLEOTIDES , *GENETIC polymorphisms , *DNA-protein interactions - Abstract
Determines the effects of single-nucleotide polymorphisms on DNA-protein interactions. Arrangement of transcription factor-binding sites; Alignment of binding sites; Variations in DNA sequences.
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- 2002
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6. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria.
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Knight, Julian C., Udalova, Irina, Hill, Adrian V.S., Greenwood, Brian M., Peshu, Norbert, Marsh, Kevin, and Kwiatkowski, Dominic
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CEREBRAL malaria , *GENETIC polymorphisms - Abstract
Genetic variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene regulation are unknown. Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles. [ABSTRACT FROM AUTHOR]
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- 1999
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7. The role of neutrophils in rheumatic disease-associated vascular inflammation.
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Wang, Lihui, Luqmani, Raashid, and Udalova, Irina A.
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SYSTEMIC lupus erythematosus , *ENDOTHELIUM diseases , *NEUTROPHILS , *CARDIOVASCULAR system , *RHEUMATISM , *IMMUNE complexes , *RHEUMATOID arthritis , *INFLAMMATION , *EXTRACELLULAR space - Abstract
Vascular pathologies underpin and intertwine autoimmune rheumatic diseases and cardiovascular conditions, and atherosclerosis is increasingly recognized as the leading cause of morbidity in conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. Neutrophils, important cells in the innate immune system, exert their functional effects in tissues via a variety of mechanisms, including the generation of neutrophil extracellular traps and the production of reactive oxygen species. Neutrophils have been implicated in the pathogenesis of several rheumatic diseases, and can also intimately interact with the vascular system, either through modulating endothelial barriers at the blood-vessel interface, or through associations with platelets. Emerging data suggest that neutrophils also have an important role maintaining homeostasis in individual organs and can protect the vascular system. Furthermore, studies using high-dimensional omics technologies have advanced our understanding of neutrophil diversity, and immature neutrophils are receiving new attention in rheumatic diseases including SLE and systemic vasculitis. Developments in genomic, imaging and organoid technologies are beginning to enable more in-depth investigations into the pathophysiology of vascular inflammation in rheumatic diseases, making now a good time to re-examine the full scope of roles of neutrophils in these processes. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Synovial single-cell heterogeneity, zonation and interactions: a patchwork of effectors in arthritis.
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Schonfeldova, Barbora, Zec, Kristina, and Udalova, Irina A
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ENDOTHELIAL cells , *SYNOVIAL membranes , *NEURONS , *INFLAMMATION , *CELLULAR signal transduction , *RHEUMATOID arthritis , *GENE expression profiling , *ARTHRITIS - Abstract
Despite extensive research, there is still no treatment that would lead to remission in all patients with rheumatoid arthritis as our understanding of the affected site, the synovium, is still incomplete. Recently, single-cell technologies helped to decipher the cellular heterogeneity of the synovium; however, certain synovial cell populations, such as endothelial cells or peripheral neurons, remain to be profiled on a single-cell level. Furthermore, associations between certain cellular states and inflammation were found; whether these cells cause the inflammation remains to be answered. Similarly, cellular zonation and interactions between individual effectors in the synovium are yet to be fully determined. A deeper understanding of cell signalling and interactions in the synovium is crucial for a better design of therapeutics with the goal of complete remission in all patients. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Digital transformations in education: Augmented reality in the classroom.
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Arkhipova, Maria V., Shutova, Natalia V., Orlova, Olga A., Zhernovaya, Oksana R., Zintsova, Yulia N., and Udalova, Irina M.
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DIGITAL transformation , *EDUCATIONAL planning , *DIGITAL technology , *EDUCATIONAL technology , *AUGMENTED reality , *COMPUTER assisted language instruction , *DIGITAL natives , *EDUCATIONAL change - Abstract
Technology brings significant changes to education, giving teachers opportunities to introduce new educational methods and strategies and build immersive learning experiences important for achieving success in the digital world. Augmented reality is an innovative educational tool, presenting information in a new way that appeals to the modern generation of digital native learners. The article evaluates the impact of augmented reality technology on motivation to learn a foreign language by higher University students. Motivation is the key to successful language learning that stimulates learners to realize their academic potential. The experiment reveals that augmented reality motivates students to learn better, influences their engagement and performance, and boosts learning indicators. This new-age technology, meeting the needs and interests of present-day generation, has a positive impact of students' attention, emotions, self-assurance and belief in academic achievement, promotes a better teacher-student understanding, and therefore opens a new dimension in education. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Regional specialization of macrophages along the gastrointestinal tract.
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Berthold, Dorothée L., Jones, Kelsey D.J., and Udalova, Irina A.
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GASTROINTESTINAL system , *SMALL intestine , *MACROPHAGES , *LARGE intestine , *DRUG target - Abstract
The tissue microenvironment is a major driver in imprinting tissue-specific macrophage functions in various mammalian tissues. As monocytes are recruited into the gastrointestinal (GI) tract at steady state and inflammation, they rapidly adopt a tissue-specific and distinct transcriptome. However, the GI tract varies significantly along its length, yet most studies of intestinal macrophages do not directly compare the phenotype and function of these macrophages in the small and large intestine, thus leading to disparities in data interpretations. This review highlights differences along the GI tract that are likely to influence macrophage function, with a specific focus on diet and microbiota. This analysis may fuel further investigation regarding the interplay between the intestinal immune system and GI tissue microenvironments, ideally providing unique therapeutic targets to modulate specific intestinal macrophage populations and/or functions. The tissue microenvironment is crucial for imprinting mammalian tissue-specific macrophage functions. The tissue microenvironment varies significantly between the small intestine and colon due to changes in nutrient availability, microbial load, oxygen availability, and mucus thickness. Monocytes recruited to the small intestine and colon adopt a tissue-specific and distinct transcriptome. Integration of cues from the immediate environment of tissue-resident macrophages leads to modulation of their functions via gene expression profiles. Dietary metabolites and spatial organization of the microbiome are underappreciated factors contributing to shaping macrophage functions along the gastrointestinal tract. [ABSTRACT FROM AUTHOR]
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- 2021
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11. Localization of a long-range cis-regulatory element of IL13 by allelic transcript ratio mapping.
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Forton, Julian T., Udalova, Irina A., Campino, Susana, Rockett, Kirk A., Hull, Jeremy, and Kwiatkowski, Dominic P.
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GENES , *GENETIC transcription , *GENETIC regulation , *GENOTYPE-environment interaction , *GENOMICS - Abstract
It appears that, for many genes, the two alleles possessed by an individual may produce different amounts of transcript. When such allelic differences in transcription are observed for some individuals but not others, a plausible explanation is genetic variation in the cis-acting elements that regulate the gene in question. Here we describe a novel analytical approach that uses such observations, combined with genotyping data from the HapMap project, to define the genomic location of cis-acting regulatory elements. When applied to the human 5q31 chromosomal region, where complex regulatory mechanisms are known to exist, we demonstrate the sensitivity of this approach by locating a highly significant cis-regulatory element operating on IL13 at long range from a position 250 kb upstream from the gene (P = 2 x 10-6). As this method is unaffected by other sources of variation, such as environmental and trans-acting genetic factors, it provides a tractable approach for dissecting the complexities of genetic variation in gene regulation. [ABSTRACT FROM AUTHOR]
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- 2007
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12. Activation and Function of Interferon Regulatory Factor 5.
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Ryzhakov, Grigory, Eames, Hayley L., and Udalova, Irina A.
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INTERFERON regulatory factors , *IMMUNE response , *NEOPLASTIC cell transformation , *AUTOIMMUNITY , *PHOSPHORYLATION , *CYTOSOL - Abstract
Interferon regulatory factor 5 (IRF5) is a crucial transcription factor in a number of immune and homeostatic processes, including host defense against pathogens, tumorigenesis, and autoimmunity. Upon induction of immune signaling pathways, IRF5 undergoes post-translational modifications such as phosphorylation and ubiqutination, which are believed to trigger IRF5 nuclear translocation from the cytosol, followed by recruitment to promoters where transcription of its gene targets is initiated. In this review, we systematically analyze the data published in the last decade on IRF5 activation, including the role of post-translational modifications and the proposed enzymes targeting IRF5 in this process. We discuss suggested models of IRF5 activation in connection to pathway-specific functions of IRF5. [ABSTRACT FROM AUTHOR]
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- 2015
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13. Evolution of Vertebrate Immunity: Sequence and Functional Analysis of the SEFIR Domain Family Member Act1.
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Ryzhakov, Grigory, Blazek, Katrina, and Udalova, Irina
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VERTEBRATE evolution , *SEQUENCE alignment , *HOMOLOGY (Biology) , *PROTEIN analysis , *GENE expression - Abstract
SEF/IL-17R/CIKS/ACT1 homology (SEFIR) domain containing proteins, which include the IL-17 receptors and an adaptor protein Act1, have essential roles in vertebrate immunity. However, the molecular mechanisms of Act1 function remain largely unexplored. In this article, we employed an evolutionary analysis to discover novel structural and functional properties of Act1. Firstly, we have found that the previously identified helix-loop-helix and Ufd2-box domains in human Act1 have relatively recent evolutionary origins in higher vertebrates. Zebrafish Act1, which lacks these domains, is unable to induce JNK phosphorylation and activate cytokine expression when expressed in human cells. Secondly, we have established that Act1-like proteins contain DEATH-domains in basal animals, such as Hydra and primitive chordates, but lack this domain in vertebrates. Finally, we have shown that Act1-TRAF6 interactions are conserved throughout vertebrate evolution: Act1 derived from zebrafish can bind to TRAF6 and activate NF-κB in human cells. Moreover, we have identified a novel highly conserved motif at the amino-terminus of Act1, which is critical for binding to TRAF6 and activating NF-κB-dependent gene expression. We propose a model of evolutionary changes in Act1-mediated signalling, which contributes to a better understanding of evolution of the vertebrate immunity. [ABSTRACT FROM AUTHOR]
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- 2011
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14. The Zinc Finger Protein Zbtb18 Represses Expression of Class I Phosphatidylinositol 3-Kinase Subunits and Inhibits Plasma Cell Differentiation.
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Bin Xie, Khoyratty, Tariq E., Abu-Shah, Enas, Cespedes, Pablo F., MacLean, Andrew J., Pirgova, Gabriela, Zhiyuan Hu, Ahmed, Ahmed A., Dustin, Michael L., Udalova, Irina A., and Arnon, Tal I.
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ZINC-finger proteins , *PLASMA cells , *CELL differentiation , *B cells , *PROMOTERS (Genetics) - Abstract
The PI3K pathway plays a key role in B cell activation and is important for the differentiation of Ab producing plasma cells (PCs). Although much is known about the molecular mechanisms that modulate PI3K signaling in B cells, the transcriptional regulation of PI3K expression is poorly understood. In this study, we identify the zinc finger protein Zbtb18 as a transcriptional repressor that directly binds enhancer/promoter regions of genes encoding class I PI3K regulatory subunits, subsequently limiting their expression, dampening PI3K signaling and suppressing PC responses. Following activation, dividing B cells progressively downregulated Zbtb18, allowing gradual amplification of PI3K signals and enhanced development of PCs. Human Zbtb18 displayed similar expression patterns and function in human B cells, acting to inhibit development of PCs. Furthermore, a number of Zbtb18 mutants identified in cancer patients showed loss of suppressor activity, which was also accompanied by impaired regulation of PI3K genes. Taken together, our study identifies Zbtb18 as a repressor of PC differentiation and reveals its previously unappreciated function as a transcription modulator of the PI3K signaling pathway. [ABSTRACT FROM AUTHOR]
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- 2021
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15. IRF5 Promotes Influenza Virus-Induced Inflammatory Responses in Human Induced Pluripotent Stem Cell-Derived Myeloid Cells and Murine Models.
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Forbester, Jessica L., Clement, Mathew, Wellington, Dannielle, Yeung, Amy, Dimonte, Sandra, Marsden, Morgan, Chapman, Lucy, Coomber, Eve L., Tolley, Charlotte, Lees, Emily, Hale, Christine, Clare, Simon, Udalova, Irina, Tao Dong, Dougan, Gordon, and Humphreys, Ian R.
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INTERFERON receptors , *HEMAGGLUTININ , *TYPE I interferons , *WEST Nile fever , *INFLUENZA , *MEDICAL sciences , *CYTOTOXIC T cells , *INTERFERON regulatory factors - Published
- 2020
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16. Caspase-8 promotes c-Rel-dependent inflammatory cytokine expression and resistance against Toxoplasma gondii.
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DeLaney, Alexandra A., Berry, Corbett T., Christian, David A., Hart, Andrew, Bjanes, Elisabet, Wynosky-Dolfi, Meghan A., Xinyuan Li, Tummers, Bart, Udalova, Irina A., Chen, Youhai H., Hershberg, Uri, Freedman, Bruce D., Hunter, Christopher A., and Brodsky, Igor E.
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TUMOR necrosis factor receptors , *TOXOPLASMA gondii , *GENETIC regulation , *TOLL-like receptors , *GENE expression , *NECROSIS - Abstract
Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Following engagement of tumor necrosis factor superfamily receptors or certain Toll-like receptors (TLRs), caspase-8 initiates cell-extrinsic apoptosis while inhibiting RIPK3-dependent programmed necrosis. In addition, caspase-8 has an important, albeit less well understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 or the adaptor FADD have defective inflammatory cytokine expression and inflammasome priming in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8-mediated gene regulation has a physiological role during infection, remain poorly defined. Here we demonstrate that both caspase-8 enzymatic activity and scaffolding functions contribute to inflammatory cytokine gene expression. Caspase- 8 enzymatic activity was necessary for maximal expression of Il1b and Il12b, but caspase-8 deficient cells exhibited a further decrease in expression of these genes. Furthermore, the ability of TLR stimuli to induce optimal IκB kinase phosphorylation and nuclear translocation of the nuclear factor kappa light chain enhancer of activated B cells family member c-Rel required caspase activity. Interestingly, overexpression of c-Rel was sufficient to restore expression of IL- 12 and IL-1β in caspase-8-deficient cells.Moreover, Ripk3-/-Casp8-/- mice were unable to control infection by the intracellular parasite Toxoplasma gondii, which corresponded to defects in monocyte recruitment to the peritoneal cavity, and exogenous IL-12 restored monocyte recruitment and protection of caspase-8-deficientmice during acute toxoplasmosis. These findings provide insight into how caspase-8 controls inflammatory gene expression and identify a critical role for caspase-8 in host defense against eukaryotic pathogens. [ABSTRACT FROM AUTHOR]
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- 2019
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17. Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.
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Seneviratne, Anusha N., Edsfeldt, Andreas, Cole, Jennifer E., Kassiteridi, Christina, Swart, Maarten, Park, Inhye, Green, Patricia, Khoyratty, Tariq, Saliba, David, Goddard, Michael E., Sansom, Stephen N., Goncalves, Isabel, Krams, Rob, Udalova, Irina A., and Monaco, Claudia
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INTERFERON regulatory factors , *ATHEROSCLEROSIS , *MACROPHAGES , *CELL culture , *BONE marrow cells - Abstract
BACKGROUND: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. METHODS: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice and ApoE-/- mice with a genetic deletion of IRF5 (ApoE-/-Irf5-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation. RESULTS: Both lesion and necrotic core size were significantly reduced in ApoE-/-Irf5-/- mice compared with IRF5-competent ApoE-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c+ macrophages was evident in ApoE-/-Irf5-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c+ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globuleepidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ. CONCLUSIONS: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis. [ABSTRACT FROM AUTHOR]
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- 2017
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18. Low shear stress induces M1 macrophage polarization in murine thin-cap atherosclerotic plaques.
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Seneviratne, Anusha N., Cole, Jennifer E., Goddard, Michael E., Park, Inhye, Mohri, Zahra, Sansom, Stephen, Udalova, Irina, Krams, Rob, and Monaco, Claudia
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MACROPHAGES , *ATHEROSCLEROTIC plaque , *SHEARING force , *CAROTID artery , *OSCILLATING chemical reactions , *LABORATORY mice - Abstract
Macrophages, a significant component of atherosclerotic plaques vulnerable to acute complications, can be pro-inflammatory (designated M1), regulatory (M2), lipid- (Mox) or Heme-induced (Mhem). We showed previously that low (LSS) and oscillatory (OSS) shear stress cause thin-cap fibroatheroma and stable smooth muscle cell-rich plaque formation respectively in ApoE-knockout (ApoE −/− ) mice. Here we investigated whether different shear stress conditions relate to specific changes in macrophage polarization and plaque morphology by applying a shear stress-altering cast to the carotid arteries of high fat-fed ApoE −/− mice. The M1 markers iNOS and IRF5 were highly expressed in macrophage-rich areas of LSS lesions compared to OSS lesions 6 weeks after cast placement, while the M2 marker Arginase-1, and Mox/Mhem markers HO-1 and CD163 were elevated in OSS lesions. Our data indicates shear stress could be an important determinant of macrophage polarization in atherosclerosis, with low shear promoting M1 programming. [ABSTRACT FROM AUTHOR]
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- 2015
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19. IRF5 controls both acute and chronic inflammation.
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Weiss, Miriam, Byrne, Adam J., Blazek, Katrina, Saliba, David G., Pease, James E., Perocheau, Dany, Feldmann, Marc, and Udalova, Irina A.
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NEUTROPHIL immunology , *MACROPHAGES , *INFLAMMATION prevention , *PHENOTYPES , *CHEMOKINES , *LABORATORY mice - Abstract
Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there is an increasing awareness that neutrophils may also play an important role. In addition to the well-documented heterogeneity of macrophage phenotypes and functions, neutrophils also show remarkable phenotypic diversity among tissues. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics.We have shown that the transcription factor IFN regulatory factor 5 (IRF5) polarizes macrophages toward an inflammatory phenotype. IRF5 is also expressed in other myeloid cells, including neutrophils, where it was linked to neutrophil function. In this study we explored the role of IRF5 in models of acute inflammation, including antigen-induced inflammatory arthritis and lung injury, both involving an extensive influx of neutrophils. Mice lacking IRF5 accumulate far fewer neutrophils at the site of inflammation due to the reduced levels of chemokines important for neutrophil recruitment, such as the chemokine (C-X-C motif) ligand 1. Furthermore we found that neutrophils express little IRF5 in the joints and that their migratory properties are not affected by the IRF5 deficiency. These studies extend prior ones suggesting that inhibiting IRF5 might be useful for chronic macrophage- induced inflammation and suggest that IRF5 blockade would ameliorate more acute forms of inflammation, including lung injury. [ABSTRACT FROM AUTHOR]
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- 2015
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20. Interferon-β Production via Dectin-1-Syk-IRF5 Signaling in Dendritic Cells Is Crucial for Immunity to C. albicans.
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del?Fresno, Carlos, Soulat, Didier, Roth, Susanne, Blazek, Katrina, Udalova, Irina, Sancho, David, Ruland, Jürgen, and Ardavín, Carlos
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INTERFERONS , *CELLULAR signal transduction , *DENDRITIC cells , *IMMUNITY , *ANTIVIRAL agents , *IMMUNOCOMPETENT cells , *CANDIDA albicans - Abstract
Summary: Type I interferon (IFN) is crucial during infection through its antiviral properties and by coordinating the immunocompetent cells involved in antiviral or antibacterial immunity. Type I IFN (IFN-α and IFN-β) is produced after virus or bacteria recognition by cytosolic receptors or membrane-bound TLR receptors following the activation of the transcription factors IRF3 or IRF7. IFN-β production after fungal infection was recently reported, although the underlying mechanism remains controversial. Here we describe that IFN-β production by dendritic cells (DCs) induced by Candida albicans is largely dependent on Dectin-1- and Dectin-2-mediated signaling. Dectin-1-induced IFN-β production required the tyrosine kinase Syk and the transcription factor IRF5. Type I IFN receptor-deficient mice had a lower survival after C. albicans infection, paralleled by defective renal neutrophil infiltration. IFN-β production by renal infiltrating leukocytes was severely reduced in C. albicans-infected mice with Syk-deficient DCs. These data indicate that Dectin-induced IFN-β production by renal DCs is crucial for defense against C. albicans infection. [Copyright &y& Elsevier]
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- 2013
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21. Cross-species Analysis Reveals Evolving and Conserved Features of the Nuclear Factor κB (NF-κB) Proteins.
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Ryzhakov, Grigory, Teixeira, Ana, Saliba, David, Blazek, Katrina, Muta, Tatsushi, Ragoussis, Jiannis, and Udalova, Irina A.
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NF-kappa B , *TRANSCRIPTION factors , *GENE expression , *SEA anemones , *DNA-binding proteins - Abstract
NF-κB is a key regulator of immune gene expression in metazoans. It is currently unclear what changes occurred in NF-κB during animal evolution and what features remained conserved. To address this question, we compared the biochemical and functional properties of NF-κB proteins derived from human and the starlet sea anemone (Nematostella vectensis) in 1) a high-throughput assay of in vitro preferences for DNA sequences, 2) ChIP analysis of in vivo recruitment to the promoters of target genes, 3) a LUMIER-assisted examination of interactions with cofactors, and 4) a transactivation assay. We observed a remarkable evolutionary conservation of the DNA binding preferences of the animal NF-κB orthologs. We also show that NF-κB dimerization properties, nuclear localization signals, and binding to cytosolic IκBs are conserved. Surprisingly, the Bcl3-type nuclear IκB proteins functionally pair up only with NF-κBderived from their own species. The basis of the differential NF-κB recognition by IκB subfamilies is discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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22. IRF5 Is a Specific Marker of Inflammatory Macrophages In Vivo.
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Weiss, Miriam, Blazek, Katrina, Byrne, Adam J., Perocheau, Dany P., and Udalova, Irina A.
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INTERFERON regulatory factors , *MACROPHAGES , *INFLAMMATION , *CYTOKINES , *NATURAL immunity , *IMMUNE system , *BIOMARKERS , *ANTI-inflammatory agents - Abstract
Macrophages are an integral part of the innate immune system and key players in pathogen clearance and tissue remodelling. Both functions are accomplished by a pivotal network of different macrophage subtypes, including proinflammatory M1 and anti-inflammatory M2 macrophages. Previously, our laboratory identified the transcription factor interferon regulatory factor 5 (IRF5) as the master regulator of the M1 macrophage polarisation. IRF5 was found to be highly expressed in human M1 compared to M2 macrophages. Furthermore, IRF5 dictates the expression of proinflammatory genes such as IL12b and IL23a whilst repressing anti-inflammatory genes like IL10. Here we show that murine bone marrow derived macrophages differentiated in vitro with GM-CSF are also characterised by high levels of IRF5 mRNA and protein and express proinflammatory cytokines upon LPS stimulation. These macrophages display characteristic expression of M1-marker MHC II but lack the M2-marker CD206. Significantly, we develop intracellular staining of IRF5- expressing macrophages and utilise it to recapitulate the in vitro results in an in vivo model of antigen-induced arthritis, emphasising their physiological relevance. Thus, we establish the species-invariant role of IRF5 in controlling the inflammatory macrophage phenotype both in vitro and in in vivo. [ABSTRACT FROM AUTHOR]
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- 2013
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23. IL-17 Receptor Adaptor Protein Act1/CIKS Plays an Evolutionarily Conserved Role in Antiviral Signaling.
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Ryzhakov, Grigory, Blazek, Katrina, Chuk-ke Lai, Cheryl, and Udalova, Irina A.
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INTERLEUKIN-17 , *ADAPTOR proteins , *ANTIVIRAL agents , *GENE expression , *RNA , *FIBROBLASTS - Abstract
Double-stranded RNA-induced antiviral gene expression in mammalian cells requires activation of IFN regulatory factor 3 (IRF3). In this study, we show that the IL-17R adaptor protein Act1/CIKS is involved in this process. Small interfering RNA-mediated knockdown of Act! in primary human skin fibroblasts specifically attenuates expression of IFN-β and IFN-stimulated antiviral genes induced by a synthetic viral mimic, polyinosinic-polycytidylic acid. Ectopic expression of Act1 potentiates the IRF3-driven expression of a synthetic reporter construct as well as the induction of antiviral genes. We demonstrate that this effect is dependent on the ability of Act1 to functionally and physically interact with 1κB kinase ϵ (IKKϵ) a known IRF3 kinase, and IRF3: 1) Act1 binds IKKϵ and IRF3; 2) Acti-induced IRF3 activation can be blocked specifically by coexpression of a catalytically inactive mutant of IKKϵ; and 3) mutants of IRF3, either lacking the C terminus or mutated at the key phosphorylation sites, important for its activation by IKKϵ, do not support Acti-dependent IRF3 activation. We also show that a zebrafish Act1 protein is able to trigger antiviral gene expression in human cells, which suggests an evolutionarily conserved function of vertebrate Act1 in the host defense against viruses. On the whole, our study demonstrates that Act1 is a component of antiviral signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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24. 302 Examining the role of nuclear factor kappa-B proteins in human cytokine gene expression: Comparison of type I and type III interferons
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Goh, FuiGoon, Thomson, Scott J.P., and Udalova, Irina A.
- Published
- 2008
- Full Text
- View/download PDF
25. Principles of dimer-specific gene regulation revealed by a comprehensive characterization of NF-?B family DNA binding.
- Author
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Siggers, Trevor, Chang, Abraham B, Teixeira, Ana, Wong, Daniel, Williams, Kevin J, Ahmed, Bilal, Ragoussis, Jiannis, Udalova, Irina A, Smale, Stephen T, and Bulyk, Martha L
- Subjects
- *
GENETIC regulation , *DNA , *DIMERS , *BINDING sites , *SURFACE plasmon resonance , *PROTEIN microarrays , *GENES - Abstract
The unique DNA-binding properties of distinct NF-?B dimers influence the selective regulation of NF-?B target genes. To more thoroughly investigate these dimer-specific differences, we combined protein-binding microarrays and surface plasmon resonance to evaluate DNA sites recognized by eight different NF-?B dimers. We observed three distinct binding-specificity classes and clarified mechanisms by which dimers might regulate distinct sets of genes. We identified many new nontraditional NF-?B binding site (?B site) sequences and highlight the plasticity of NF-?B dimers in recognizing ?B sites with a single consensus half-site. This study provides a database that can be used in efforts to identify NF-?B target sites and uncover gene regulatory circuitry. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
26. IL-17 Boosts Proinflammatory Outcome of Antiviral Response in Human Cells.
- Author
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Ryzhakov, Grigory, Lai, Cheryl Chuk-ke, Blazek, Katrina, To, Ken-win, Hussell, Tracy, and Udalova, Irina
- Abstract
Excessive inflammation during bacterial and viral infections is destructive to the host and involves elevated production of proinflammatory cytokines. It is especially deleterious in organs with space constraints such as lung and the CNS. Indeed, a number of viruses that infect lungs, such as avian influenza virus, SARS-associated coronavirus, and respiratory syncytial virus, elicit a very high level of proinflammatory cytokines; however, it is unclear what triggers their production. In this study, we show that IL-17 commonly produced during viral infection specifically augments a proinflammatory response by directly synergizing with antiviral signaling. Costimulation of primary human fibroblasts with IL-17 greatly enhanced respiratory syncytial virus-induced or synthetic dsRNA-based viral mimic polyinosinic:polycytidylic acid-induced expression of proinflammatory genes without affecting expression of IFN-ß-stimulated or IFN-stimulated genes. Knockdown of expression of known mediators of the antiviral signaling pathway revealed that the IL-17-poly(I:C) synergy depends on the presence of the transcriptional factors RelA and IFN regulatory factor 3 and IB kinases. Moreover, this synergy was blocked by an IB kinase inhibitor, BAY 11-7082. These findings shed light on the molecular mechanisms behind IL-17-dependent immunopathology observed in viral infections. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
27. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.
- Author
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Krausgruber, Thomas, Blazek, Katrina, Smallie, Tim, Alzabin, Saba, Lockstone, Helen, Sahgal, Natasha, Hussell, Tracy, Feldmann, Marc, and Udalova, Irina A
- Subjects
- *
MACROPHAGES , *GENETIC polymorphisms , *TRANSCRIPTION factors , *GENE expression , *INFLAMMATION , *INTERLEUKINS , *PHENOTYPES - Abstract
Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (TH1)-TH17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
28. Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients.
- Author
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Haralambous, Elene, Dolly, Saoirse O., Hibberd, Martin L., Litt, David J., Udalova, Irina A., O'dwyer, Cliona, Langford, Paul R., Simon Kroll, J., and Levin, Michael
- Subjects
- *
MENINGITIS , *DISEASE susceptibility , *NEISSERIA meningitidis , *COMPLEMENT (Immunology) - Abstract
Defence against Neisseria meningitidis involves complement-mediated bactericidal activity. Factor H (fH) down-regulates complement activation. A putatively functional single-nucleotide-polymorphism (SNP) exists within a presumed nuclear-factor-kappa-B responsive element (NF-kB) in the fH gene (C-496T). Genetic and functional investigations were carried out to determine whether C-496T has a role in meningococcal disease (MD) susceptibility. Genetic susceptibility was investigated in 2 independent studies, a case-control and family-based transmission-disequilibrium-test (TDT), using 2 separate cohorts of UK Caucasian patients. MD susceptibility was both genetically associated with the C/C homozygous genotype (OR = 2.0, 95% CI 1.3 – 3.2, p = 0.001) and linked to the C allele ( p = 0.04), the association being most significant in serogroup C infected patients (OR = 2.9, 95% CI 1.6 – 5.5, p = 0.0002). FH serum concentrations were also associated with C-496T genotype, with highest fH concentrations in C/C homozygous individuals ( p = 0.01). Functional studies showed NF-kappa-B binding to the C-496T-containing region and that pre-incubation of fH with meningococci reduced bactericidal activity and increased meningococci B and C survival in blood. This study shows that C-496T is both associated and linked with MD and that individuals possessing the fH C-496T C/C genotype are more likely to have increased serum fH protein levels, have reduced bactericidal activity against meningococci and be at an increased risk of contracting MD. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
29. Implications of inter-population linkage disequilibrium patterns on the approach to a disease association study in the human MHC class III.
- Author
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Hanchard, Neil, Diakite, Mahamadou, Koch, Oliver, Keating, Brendan, Pinder, Margaret, Jallow, Muminatou, Sisay-Joof, Fatou, Nijnik, Anastasia, Wilson, Jonathan, Udalova, Irina, Kwiatkowski, Dominic, and Rockett, Kirk
- Subjects
- *
ETIOLOGY of diseases , *MAJOR histocompatibility complex , *HUMAN genome , *HUMAN chromosomes , *HUMAN gene mapping - Abstract
There is presently much interest in utilizing patterns of linkage disequilibrium (LD) to further genetic association studies. This is particularly pertinent in the class III region of the human major histocompatibility complex (MHC), which has been extensively studied as a disease susceptibility locus in a number of ethnic groups. To date, however, few studies of LD in the MHC have considered non-Caucasian populations. With the advent of large-scale haplotyping of the human genome, the question of utilizing LD patterns across populations has come to the fore. We have previously used LD mapping to direct an MHC class III association study in a UK Caucasian population. As an extension of this, we sought to determine to what extent the pattern of LD observed in that study could be used to conduct a similar study in a West African Gambian population. We found that broad patterns of LD were similar in the two populations, resulting in similar candidate region delineations, but at a higher resolution, marker-specific patterns of LD and population-dependent allele frequencies confounded the choice of regional tagging SNPs. Our results have implications for the applicability of large-scale haplotype maps such as the HapMap to complex regions like the MHC. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
30. Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.
- Author
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Seneviratne, Anusha N, Edsfeldt, Andreas O, Cole, Jennifer E, Kassiteridi, Christina, Swart, Maarten, Park, Inhye, Green, Patricia, Khoyratty, Tariq E, Saliba, David G, Goddard, Michael E, Sansom, Stephen N, Goncalves, Isabel, Krams, Rob, Udalova, Irina A, Monaco, Claudia, Edsfeldt, Andreas, Khoyratty, Tariq, and Saliba, David
- Abstract
Background: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions.Methods: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice and ApoE-/- mice with a genetic deletion of IRF5 (ApoE-/-Irf5-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation.Results: Both lesion and necrotic core size were significantly reduced in ApoE-/-Irf5-/- mice compared with IRF5-competent ApoE-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c+ macrophages was evident in ApoE-/-Irf5-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c+ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ.Conclusions: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
31. Corrigendum to “Low shear stress induces M1 macrophage polarization in murine thin-cap atherosclerotic plaques” [J Mol Cell Cardiol] 89B (2015) 168–172.
- Author
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Seneviratne, Anusha N., Cole, Jennifer E., Goddard, Michael E., Park, Inhye, Mohri, Zahra, Sansom, Stephen, Udalova, Irina, Krams, Rob, and Monaco, Claudia
- Subjects
- *
PUBLISHED errata , *SHEARING force , *MACROPHAGES , *ATHEROSCLEROTIC plaque , *LABORATORY mice , *MOLECULAR cardiology - Published
- 2016
- Full Text
- View/download PDF
32. PS2-062. Novel role of IRF5 in transcriptional inhibition of human IL-10 gene expression
- Author
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Krausgruber, Thomas, Saliba, David, Eames, Hayley, Williams, Lynn, Smallie, Tim, Blazek, Katrina, and Udalova, Irina A
- Published
- 2011
- Full Text
- View/download PDF
33. SS5-2 IRF5 as a defining factor of M1 macrophage polarization
- Author
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Krausgruber, Thomas, Saliba, David, Blazek, Katrina, Lockstone, Helen, Sahgal, Natasha, Alzabin, Saba, Teixeira, Ana, Hussell, Tracy, Ragoussis, Jiannis, and Udalova, Irina A.
- Published
- 2010
- Full Text
- View/download PDF
34. PS1-75 IL-17 stimulation results in a pro-inflammatory outcome during antiviral response in human cells
- Author
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Ryzhakov, Grigory, Lai, Cheryl, Blazek, Katrina, and Udalova, Irina
- Published
- 2010
- Full Text
- View/download PDF
35. 296 Role of interferon regulatory factor 5 in regulation of the human tumor necrosis factor gene expression
- Author
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Krausgruber, Thomas, Thomson, Scott JP., Saliba, David G., and Udalova, Irina A.
- Published
- 2008
- Full Text
- View/download PDF
36. 176 Identification of a novel enhancer region in the distal promoter region of the human interferon-lambda1 gene
- Author
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Thomson, Scott J.P., Goh, FuiGoon, Banks, Helen, Foxwell, Brian, Kotenko, Sergei V., and Udalova, Irina A.
- Published
- 2008
- Full Text
- View/download PDF
37. Functional conservation of Rel binding sites in drosophilid genomes.
- Author
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Copley, Richard R., Totrov, Maxim, Linnell, Jane, Field, Simon, Ragoussis, Jiannis, and Udalova, Irina A.
- Subjects
- *
GENETIC regulation , *TRANSCRIPTION factors , *NUCLEOTIDE sequence , *DROSOPHILA , *AMINO acids , *GENOMES - Abstract
Evolutionary constraints on gene regulatory elements are poorly understood: Little is known about how the strength of transcription factor binding correlates with DNA sequence conservation, and whether transcription factor binding sites can evolve rapidly while retaining their function. Here we use the model of the NFKB/Rel-dependent gene regulation in divergent Drosophila species to examine the hypothesis that the functional properties of authentic transcription factor binding sites are under stronger evolutionary constraints than the genomic background. Using molecular modeling we compare tertiary structures of the Drosophila Rel family proteins Dorsal, Dif, and Relish and demonstrate that their DNA-binding and protein dimerization domains undergo distinct rates of evolution. The accumulated amino acid changes, however, are unlikely to affect DNA sequence recognition and affinity. We employ our recently developed microarray-based experimental platform and principal coordinates statistical analysis to quantitatively and systematically profile DNA binding affinities of three Drosophila Rel proteins to 10,368 variants of the NFKB recognition sequences. We then correlate the evolutionary divergence of gene regulatory regions with differences in DNA binding affinities. Genome-wide analyses reveal a significant increase in the number of conserved Rel binding sites in promoters of developmental and immune genes. Significantly, the affinity of Rel proteins to these sites was higher than to less conserved sites and was maintained by the conservation of the DNA binding site sequence (static conservation) or in some cases despite significantly diverged sequences (dynamic conservation). We discuss how two types of conservation may contribute to the stabilization and optimization of a functional gene regulatory code in evolution. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
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