Interferon regulatory factor 5: a potential target for therapeutic intervention in inflammatory diseases

Abstract

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the IRF family, playing a pivotal role in modulating immune responses, particularly within the innate immune system. IRF5 regulates the expression of type I interferons (IFNs), proinflammatory cytokines, and other immune-related genes, essential for effective host defense against infections and immune surveillance. Its functions, however, are diverse and highly context-dependent, adapting to different immune challenges and tissue environments. Studies have demonstrated that dysregulated IRF5 activation contributes to the pathogenesis of numerous diseases, including cancer, autoimmune disorders, and chronic inflammatory conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This dysregulation underscores the dual role of IRF5, both in immune protection and in driving pathological inflammation. Given its significant involvement in both physiological and pathological processes, IRF5 presents a promising therapeutic target for managing diseases characterized by excessive inflammation and immune dysregulation. However, developing effective molecules to specifically modulate the IRF5 pathway remains challenging, with limited therapeutic agents available for clinical application. In this review, we examine the diverse roles of IRF5 in various disease contexts, the mechanisms by which IRF5 contributes to disease progression, and the potential therapeutic strategies targeting IRF5. Additionally, we discuss potential complications and risks associated with IRF5-targeted therapies, including the balance between dampening pathological inflammation and preserving essential immune functions. This exploration highlights both the therapeutic potential and the complexity of modulating IRF5 activity in clinical settings.

Keywords: IRF5; autoimmune diseases; cytokines; inflammatory diseases; tumorigenesis.

Figure 1

Strategies to regulate the expression of IRF5. (From left to right) IRF5 knockout in human-induced pluripotent stem cell-derived macrophages using the CRISPR/Cas9 system. Adenoviral vectors delivered IRF5 genes to increase IRF5 expression. IRF5 expression was modulated by RNA interference (RNAi) using small interfering RNA (siRNA) -mediated therapy delivered by lipid-like nanoparticles (LLN). After stimulation with Toll-like receptor 7 (TLR7), TRIpartite motif 21 (TRIM21) regulates IRF5 stability and activity in an isotype-specific manner.

Figure 2

Strategies to inhibit IRF5. 4F competed for access to IRF5 to inhibit its activation and promote its degradation. N5-1 stabilizes the inactive monomer, inhibiting its homodimerization and nuclear translocation. IRF5D targets IRF5 and prevents its nuclear translocation. Heme inhibits the IRF5/RelA interaction to down-regulate inflammation.