Advances and challenges in targeting IRF5, a key regulator of inflammation

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.

A RUNX3 enhancer polymorphism associated with ankylosing spondylitis influences recruitment of Interferon Regulatory Factor 5 and factors of the Nucleosome Remodelling Deacetylase Complex in CD8+ T-cells

“…The potential benefits of modulating IRF5 expression, its post-translational modification and/or functional interactions with its protein partners for therapeutic benefit have been extensively discussed elsewhere. [17] Increased binding of the chromatin reader BRD4, also to the ASprotective allele G (Bromodomain Containing 4, see Supplementary Table 1), reinforces the likely contribution to AS of factors involved in transcriptional control and epigenetic regulation at RUNX3. [20] The approach we have adopted here is a first step towards understanding the mechanisms underlying one of the strongest genetic associations with AS and the role of RUNX3 in its pathogenesis.…”

“…IRF5 is of considerable interest in inflammatory states: it plays a central role in the induction of inflammatory cytokines, such IL6, IL12, IL23 and tumour necrosis factor α. [17] It is also a key factor in determining inflammatory macrophage phenotypes in response to stimulation by interferon γ and granulocyte-macrophage stimulating factor, which is now thought to be a key factor in the development of AS. [18] IRF5 is also strongly associated genetically with other inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis and inflammatory bowel disease, where it is associated with insertion/deletion mutations creating an Sp1 binding site that upregulates IRF5 expression.…”

Development and validation of a novel stem cell subtype for bladder cancer based on stem genomic profiling

“…Two pairs of transcription factor regulators were identified in the brown and black modules ( Figure 10B-C), IRF5 and GATA3 and GRHL2 and GATA6. IRF5 is a key transcription factor regulating the differentiation of M1 macrophages into M2 macrophages, enabling M2 macrophages to play an anti-inflammatory role; these cells also have an important role in tissue repair and reconstruction and cancer occurrence [33][34][35]. GATA3 is type 2 helper T cell (Th2) cytokine-specific transcription factor and a key stemness gene that regulates cell differentiation.…”

Development and validation of a novel stem cell subtype for bladder cancer based on stem genomic profiling

“…Two pairs of transcription factor regulators were identi ed in the brown and black modules ( Figure 10B-C), IRF5 and GATA3 and GRHL2 and GATA6. IRF5 is a key transcription factor regulating the differentiation of M1 macrophages into M2, enabling its anti-in ammatory role; these cells also in uence tissue repair and reconstruction as well as cancer occurrence [41][42][43]. GATA3 is a type 2 helper T cell (Th2) cytokinespeci c transcription factor and a key stemness gene that regulates cell differentiation.…”