An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice

Weihrauch, Dorothée; Krolikowski, John G.; Jones, Deron W.; Zaman, Tahniyath; Bamkole, Omoshalewa; Struve, Janine; Pagel, Paul S.; Lohr, Nicole L.; Pritchard, Kirkwood A.

doi:10.1371/journal.pone.0151999

Cited by 10 publications

(16 citation statements)

References 27 publications

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“…Altogether, these data show that IRF5 represents a particularly valuable, dual-function therapeutic target to treat autoimmune and inflammatory diseases. To date, this is the first report to our knowledge of a selective IRF5 inhibitor that directly binds to IRF5 to inhibit nuclear translocation and has in vivo clinical efficacy in murine models of lupus (39,83,84).…”

Section: Discussionmentioning

confidence: 94%

Inhibition of IRF5 hyperactivation protects from lupus onset and severity

Su¹,

De²,

Nelson³

et al. 2020

Journal of Clinical Investigation

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Authorship note: S. Song and SD are co-first authors. Conflict of interest: BJB is an inventor on a US patent application (US20200071370A1, Cell-penetrating peptides that inhibit IRF5 nuclear localization), assigned to Rutgers. BJB and S. Sun are inventors on a US provisional patent application (62/844,894, Inhibition of IRF5 protects from lupus onset and severity), assigned to Feinstein Institutes.

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Section: Discussionmentioning

confidence: 94%

Inhibition of IRF5 hyperactivation protects from lupus onset and severity

Su¹,

De²,

Nelson³

et al. 2020

Journal of Clinical Investigation

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“…More recently, alterations of IRF5 levels were also linked to obesity and its comorbidities such as nonalcoholic liver disease (NASH) and type 2 diabetes . Interestingly, protective effects seen in IRF5 ko mice are due to the defect of its repressive activity, emphasizing therapeutic opportunities via manipulating IRF activity, in line with recent attempts to develop decoy peptide inhibitors .…”

Section: Context Matters: How Irf5 Activation Versus Repression Pathwmentioning

confidence: 92%

Transcriptional repression in macrophages—basic mechanisms and alterations in metabolic inflammatory diseases

et al. 2017

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Macrophage differentiation and signal responses are coordinated by closely linked transcriptional and epigenomic mechanisms that trigger gene expression. In contrast to well-characterized transcriptional activation pathways in response to diverse metabolic and inflammatory signals, we just begin appreciating that transcriptional repression is equally important. Here, we will highlight macrophage pathways that are controlled by multifaceted repression events, along with a discussion of underlying regulatory mechanisms and components. We will particularly discuss pro-versus anti-inflammatory action of a fundamental corepressor complex, transcription factor cross-talk, repression at enhancers and during elongation, and diverse corepressor knockout mouse models. We will finally emphasize how alterations of macrophage repression pathways in humans contribute to, or even cause, metabolic inflammatory diseases such as obesity and type 2 diabetes.

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“…The homodimeric figure is presented for easier viewing of the region where the phosphorylated tail domain of IRF5 binds to form a homodimer. This figure has been previously published 21 .…”

Section: Figurementioning

confidence: 95%

“…Analysis software showed that IRF5 binds to IRF5D with a K d of 3.72 ± 0.75 × 10 −6 M (mean ± SD, n = 3). This figure has been previously published 21 .…”

Section: Figurementioning

confidence: 95%

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Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice

Weihrauch

Krolikowski

Jones³

et al. 2017

JoVE

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The interferon regulatory factor 5 (IRF5) is crucial for cells to determine if they respond in a pro-inflammatory or anti-inflammatory fashion. IRF5’s ability to switch cells from one pathway to another is highly attractive as a therapeutic target. We designed a decoy peptide IRF5D with a molecular modeling software for designing small molecules and peptides. IRF5D inhibited IRF5, reduced alterations in extracellular matrix, and improved endothelial vasodilation in the tight-skin mouse (Tsk/+). The Kd of IRF5D for recombinant IRF5 is 3.72 ± 0.74 × 10−6 M as determined by binding experiments using biolayer interferometry experiments. Endothelial cells (EC) proliferation and apoptosis were unchanged using increasing concentrations of IRF5D (0 to 100 μg/mL, 24 h). Tsk/+ mice were treated with IRF5D (1 mg/kg/d subcutaneously, 21 d). IRF5 and ICAM expressions were decreased after IRF5D treatment. Endothelial function was improved as assessed by vasodilation of facialis arteries from Tsk/+ mice treated with IRF5D compared to Tsk/+ mice without IRF5D treatment. As a transcription factor, IRF5 traffics from the cytosol to the nucleus. Translocation was assessed by immunohistochemistry on cardiac myocytes cultured on the different cardiac extracellular matrices. IRF5D treatment of the Tsk/+ mouse resulted in a reduced number of IRF5 positive nuclei in comparison to the animals without IRF5D treatment (50 μg/mL, 24 h). These findings demonstrate the important role that IRF5 plays in inflammation and fibrosis in Tsk/+ mice.

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An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice

Cited by 10 publications

References 27 publications

Inhibition of IRF5 hyperactivation protects from lupus onset and severity

Inhibition of IRF5 hyperactivation protects from lupus onset and severity

Transcriptional repression in macrophages—basic mechanisms and alterations in metabolic inflammatory diseases

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice

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