IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitors

Shu, Jin; Li, Ling; Zhou, Lan‐Bo; Qian, Jun; Fan, Zhidan; Zhuang, Lili; Wang, Lulu; Jin, Rui; Yu, Haiguo; Zhou, Guoping

doi:10.18632/oncotarget.17586

Cited by 15 publications

(8 citation statements)

References 41 publications

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“…In the case of SLE, GWAS across multiple ancestral backgrounds have confirmed that IRF5 polymorphisms associate with SLE risk [( 60 , 63 – 66 )]. In SLE patient blood, IRF5 expression and activation were found to be significantly elevated ( 67 – 71 ). Prior to these findings, IRF5 was identified as a critical mediator of MyD88-dependent TLR signaling, leading to the expression/production of multiple pro-inflammatory cytokines including type I IFNs, IL6, TNFα, IL12, IL23, and others implicated in autoimmune disease pathogenesis ( 62 , 72 – 76 ).…”

Section: Implications For Irfs In Disease Pathogenesis–why Target Thementioning

confidence: 99%

Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

2018

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The interferon regulatory factors (IRFs) are a family of master transcription factors that regulate pathogen-induced innate and acquired immune responses. Aberration(s) in IRF signaling pathways due to infection, genetic predisposition and/or mutation, which can lead to increased expression of type I interferon (IFN) genes, IFN-stimulated genes (ISGs), and other pro-inflammatory cytokines/chemokines, has been linked to the development of numerous diseases, including (but not limited to) autoimmune and cancer. What is currently lacking in the field is an understanding of how best to therapeutically target these transcription factors. Many IRFs are regulated by post-translational modifications downstream of pattern recognition receptors (PRRs) and some of these modifications lead to activation or inhibition. We and others have been able to utilize structural features of the IRFs in order to generate dominant negative mutants that inhibit function. Here, we will review potential therapeutic strategies for targeting all IRFs by using IRF5 as a candidate targeting molecule.

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Section: Implications For Irfs In Disease Pathogenesis–why Target Thementioning

confidence: 99%

Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

2018

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“…In PBMCs from patients with jSLE, mRNA expression of IRF5, IFN-α and Sp1 is increased. Exposure of cells to HDAC (histone deacetylase) inhibitor TSA (trichostatin A) or forced histone acetylase p300 expression repressed IRF5 promoter activity, suggesting the use of HDACi (HDAC inhibitor) as a potential future therapeutic option in SLE [ 109 ].…”

Section: Introductionmentioning

confidence: 99%

Systemic Lupus Erythematosus in Children and Young People

2021

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Purpose of Review Juvenile-onset systemic lupus erythematosus ((j)SLE) is an autoimmune/inflammatory disease that results in significant damage and disability. When compared to patients with disease onset in adulthood, jSLE patients exhibit increased disease activity, damage and require more aggressive treatments. This manuscript summarises age-specific pathogenic mechanisms and underscores the need for age group–specific research, classification and treatment. Recent Findings Genetic factors play a significant role in the pathophysiology of jSLE, as > 7% of patients develop disease as a result of single gene mutations. Remaining patients carry genetic variants that are necessary for disease development, but require additional factors. Increased ‘genetic impact’ likely contributes to earlier disease onset and more severe phenotypes. Epigenetic events have only recently started to be addressed in jSLE, and add to the list of pathogenic mechanisms that may serve as biomarkers and/or treatment targets. To allow meaningful and patient-oriented paediatric research, age-specific classification criteria and treatment targets require to be defined as currently available tools established for adult-onset SLE have limitations in the paediatric cohort. Summary Significant progress has been made in understanding the pathophysiology of jSLE. Meaningful laboratory and clinical research can only be performed using age group–specific tools, classification criteria and treatment targets.

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“…It is also involved in adaptive and innate immunity. The first identified single-nucleotide polymorphism (SNP) in IRF5, Rs2004640, is closely related to the high expression of several IRF5 isoforms and is a valuable genetic risk factor for SLE (23).…”

Section: Discussionmentioning

confidence: 99%

Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects

Arneth

2019

Front. Immunol.

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Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the production of autoantibodies specific for components of the cell nucleus and that causes damage to body tissues and organs. The pathogenesis of SLE remains unclear, with numerous studies pointing to a combination of genetic and environmental factors. A critical stage in SLE development is cell necrosis, in which undegraded chromatin and nucleoproteins are released into the blood, resulting in circulating cell-free DNA and serum nucleoproteins that trigger anti-dsDNA autoantibody production. This systematic literature review aimed to examine whether SLE stems from a DNA degradation and elimination defect. Materials and Methods: An advanced literature search was conducted in PubMed using the following keywords: [(“SLE” OR “Systemic Lupus Erythematosus” OR “Lupus”)] AND [(“DNA” OR “DNA Degradation”)] AND [(“Defect Elimination”)]. More articles were obtained from the references of the identified articles and basic Google searches. Twenty-five peer-reviewed articles published within the past 10 years (2007–2018) were included for review. Results: The findings of each study are summarized in Tables 1 , 2 . Discussion and Conclusion: The etiopathogenesis of SLE remains controversial, which limits therapeutic inventions for this disease. However, SLE is a DNA degradation and elimination disorder caused by uncleared histones and nuclear material that leak into the extracellular space and form cell-free DNA, triggering an immune response that destroys tissues and organs. Under normal conditions, apoptosis allows DNA and other nuclear material to be efficiently cleared through degradation and additional complex mechanisms such that this material does not trigger the immune system to produce nuclear autoantibodies.

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IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitors

Cited by 15 publications

References 41 publications

Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

Systemic Lupus Erythematosus in Children and Young People

Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects

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