Abstract
Interferon regulatory factor 5 (IRF5) has been called a “master switch” for its ability to determine whether cells mount proinflammatory or anti-inflammatory responses. Accordingly, IRF5 should be an attractive target for therapeutic drug development. Here we report on the development of a novel decoy peptide inhibitor of IRF5 that decreases myocardial inflammation and improves vascular endothelial cell (EC) function in tight-skin (Tsk/+) mice. Biolayer interferometry studies showed the Kd of IRF5D for recombinant IRF5 to be 3.72 ± 0.74x10-6M. Increasing concentrations of IRF5D (0–100 μg/mL, 24h) had no significant effect on EC proliferation or apoptosis. Treatment of Tsk/+ mice with IRF5D (1mg/kg/d subcutaneously, 21d) reduced IRF5 and ICAM-1 expression and monocyte/macrophage and neutrophil counts in Tsk/+ hearts compared to expression in hearts from PBS-treated Tsk/+ mice (p<0.05). EC-dependent vasodilatation of facialis arteries isolated from PBS-treated Tsk/+ mice was reduced (~15%). IRF5D treatments (1mg/kg/d, 21d) improved vasodilatation in arteries isolated from Tsk/+ mice nearly 3-fold (~45%, p<0.05), representing nearly 83% of the vasodilatation in arteries isolated from C57Bl/6J mice (~55%). IRF5D (50μg/mL, 24h) reduced nuclear translocation of IRF5 in myocytes cultured on both Tsk/+ cardiac matrix and C57Bl/6J cardiac matrix (p<0.05). These data suggest that IRF5 plays a causal role in inflammation, fibrosis and impaired vascular EC function in Tsk/+ mice and that treatment with IRF5D effectively counters IRF5-dependent mechanisms of inflammation and fibrosis in the myocardium in these mice.
Highlights
Interferon regulatory factor 5 (IRF5) is a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon and regulation of cell growth, differentiation, and apoptosis and modulation of immune system activity
Our studies showed that IRF5D binds to IRF5, does not affect caspase activity and proliferation, reduces myocardial inflammation and improves vascular function in Tsk/+ mice, reduces IRF5 translocation to the nucleus
The fact that IRF5D is derived from the binding tail of IRF5, mimics activated IRF5 and reduces myocardial inflammation and improves endothelial cell (EC)-dependent vasodilatation in Tsk/+ mice provides strong support for the idea that IRF5D targets IRF5
Summary
IRF5 is a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon and regulation of cell growth, differentiation, and apoptosis and modulation of immune system activity. In recent years it has been reported that IRF5 controls the balance between type-1 and type-2 immune responses. Because type-1 responses promote inflammation and destruction of pathogens and type-2 responses promote tissue repair and growth, the ability of IRF5 to mediate the balance between these pathways earned it the reputation of being a “master switch” in immunology. Chronic IRF5 activation enhances apoptosis, a characteristic feature of cancer [1] as well as autoimmune disorders such as inflammatory bowel disease, lupus erythematosus and scleroderma [2,3,4]. Marked increases in fibrosis of the skin and internal organs concomitant with enhanced apoptosis, characterize this dreadful disease. One of the clinical features of SSc is a marked increase in myocardial inflammation, fibrosis and heart failure [9,10,11,12,13]. Tight skin (Tsk/+) mice, a murine model of autoimmunity, inflammation and fibrosis that has been used to study mechanisms of SSc [12,14], develop myocardial inflammation and fibrosis and heart failure in ways that mimic heart disease in humans with SSc [15,16,17]
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