Inhibition of IRF5 hyperactivation protects from lupus onset and severity

Su, Song; De, Saurav; Nelson, Victoria L.; Chopra, Samin; LaPan, Margaret; Kampta, Kyle; Sun, Shan; He, Mingzhu; Thompson, Cherrie D.; Li, Dan; Shih, Tiffany; Tan, Natalie Wh; Al‐Abed, Yousef; Capitle, Eugenio; Aranow, Cynthia; Mackay, Meggan; Clapp, William L.; Barnes, Betsy J.

doi:10.1172/jci120288

Cited by 52 publications

(44 citation statements)

References 83 publications

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“…To substantiate the findings of our in silico analysis by in vivo experiments, we characterize the role of one of the candidates in more detail. We selected IRF8, given that the related protein IRF5 can chemically be inhibited [23], suggesting that IRF8 could possibly be targeted in the future, as well. IRF8 has previously been described as a tumor suppressor [17,18], while our data suggest an oncogenic function in AML.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work suggests that also transcription factors [7], including interferon regulatory factors [23], can potentially be targeted by small molecule inhibitors. The development of inhibitors for transcription factors is typically more challenging compared to enzyme inhibitors, given that no enzymatic pocket exists that could easily be targeted.…”

Section: Discussionmentioning

confidence: 99%

“…As we were able to identify a putative pro-proliferative and negative prognostic role of IRF8 in AML, we hypothesized that IRF8′s role in AML might vary from its function in other cancer types. As an inhibitor for the related protein IRF5 was recently described [23,24], IRF8 may also be a suitable drug target. Therefore, we decided to investigate the role of IRF8 in AML in more detail.…”

Section: Irf8 Is a Susceptibility Gene Candidate In Amlmentioning

confidence: 99%

“…Thus, IRF8 may act distinctly in AML compared to other cancer types, which warrants further investigation. Importantly, a peptide inhibitor for the related protein IRF5 has recently been described [23], suggesting that the members of the IRF protein family are potentially suitable for chemical inhibition [24].…”

Section: Introductionmentioning

confidence: 99%

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IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

Liss

Frech

Wang

et al. 2021

Cancers

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Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells and its deletion leads to impaired proliferation in those cells. Consistently, high IRF8 expression is associated with poorer patients’ prognoses. Combining gene expression changes upon IRF8 deletion and the genome-wide localization of IRF8 in the AML cell line MV4-11, we demonstrate that IRF8 directly regulates key signaling molecules, such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5, and the cell cycle regulator Cyclin D1. IRF8 loss impairs AML-driving signaling pathways, including the WNT, Chemokine, and VEGF signaling pathways. Additionally, many members of the focal adhesion pathway showed reduced expression, providing a putative link between high IRF8 expression and poor prognosis. Thus, this study suggests that IRF8 could serve as a biomarker and potential molecular target in a subset of human AMLs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Irf8 Is a Susceptibility Gene Candidate In Amlmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

Liss

Frech

Wang

et al. 2021

Cancers

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“…IRF5 expression is upregulated in SLE patients and this enhanced expression was associated with the risk haplotype of IRF5 ( 179 ). IRF5-deficient mice or SLE model mice treated with an IRF5 inhibitor attenuated lupus pathology ( 180 , 181 ). Ex vivo human studies demonstrated that an IRF5 inhibitor blocked SLE serum-induced IRF5 activation in healthy immune cells and significantly reduced basal IRF5 hyper-activation in SLE immune cells ( 181 ).…”

Section: Roles Of Nucleic Acid Sensors In Inflammatory Diseasesmentioning

confidence: 99%

Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

2021

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Recognition of pathogen-derived nucleic acids by pattern-recognition receptors (PRRs) is essential for eliciting antiviral immune responses by inducing the production of type I interferons (IFNs) and proinflammatory cytokines. Such responses are a prerequisite for mounting innate and pathogen-specific adaptive immune responses. However, host cells also use nucleic acids as carriers of genetic information, and the aberrant recognition of self-nucleic acids by PRRs is associated with the onset of autoimmune or autoinflammatory diseases. In this review, we describe the mechanisms of nucleic acid sensing by PRRs, including Toll-like receptors, RIG-I-like receptors, and DNA sensor molecules, and their signaling pathways as well as the disorders caused by uncontrolled or unnecessary activation of these PRRs.

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Integrative Functional Genomics Identifies Systemic Lupus Erythematosus Causal Genetic Variant in the IRF5 Risk Locus

Hou

Zhou

et al. 2023

Arthritis & Rheumatology

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Objective IRF5 plays a crucial role in the development of lupus. Genome‐wide association studies have identified several systemic lupus erythematosus (SLE) risk single‐nucleotide polymorphisms (SNPs) enriched in the IRF5 locus. However, no comprehensive genome editing–based functional analysis exists to establish a direct link between these variants and altered IRF5 expression, particularly for enhancer variants. This study was undertaken to dissect the regulatory function and mechanisms of SLE IRF5 enhancer risk variants and to explore the utilization of clustered regularly interspaced short palindromic repeat interference (CRISPRi) to regulate the expression of disease risk gene to intervene in the disease. Methods Epigenomic profiles and expression quantitative trait locus analysis were applied to prioritize putative functional variants in the IRF5 locus. CRISPR‐mediated deletion, activation, and interference were performed to investigate the genetic function of rs4728142. Allele‐specific chromatin immunoprecipitation–quantitative polymerase chain reaction and allele‐specific formaldehyde‐assisted isolation of regulatory element–quantitative polymerase chain reaction were used to decipher the mechanism of alleles differentially regulating IRF5 expression. The CRISPRi approach was used to evaluate the intervention effect in monocytes from SLE patients. Results SLE risk SNP rs4728142 was located in an enhancer region, indicating a disease‐related regulatory function, and risk allele rs4728142‐A was closely associated with increased IRF5 expression. We demonstrated that an rs4728142‐containing region could act as an enhancer to regulate the expression of IRF5. Moreover, rs4728142 affected the binding affinity of zinc finger and BTB domain–containing protein 3 (ZBTB3), a transcription factor involved in regulation. Furthermore, in monocytes from SLE patients, CRISPR‐based interference with the regulation of this enhancer attenuated the production of disease‐associated cytokines. Conclusion These results demonstrate that the rs4728142‐A allele increases the SLE risk by affecting ZBTB3 binding, chromatin status, and regulating IRF5 expression, establishing a biologic link between genetic variation and lupus pathogenesis.

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Inhibition of IRF5 hyperactivation protects from lupus onset and severity

Cited by 52 publications

References 83 publications

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

Integrative Functional Genomics Identifies Systemic Lupus Erythematosus Causal Genetic Variant in the IRF5 Risk Locus

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