Interferon regulatory factor signaling in autoimmune disease

Matta, Bharati; Su, Song; Li, Dan; Barnes, Betsy J.

doi:10.1016/j.cyto.2017.02.006

Cited by 30 publications

(28 citation statements)

References 166 publications

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“…Limited and not very well-replicated studies have reported an association of IRF2 polymorphism with susceptibility to the autoimmune disease systemic lupus erythematosus (SLE). The SLE risk haplotype was suggested to be associated with activation of IRF2 ( 17 , 30 , 31 ).…”

Section: Implications For Irfs In Disease Pathogenesis–why Target Thementioning

confidence: 99%

“…Similarly, IRF3 polymorphisms were found to be associated with SLE but controversy still exists regarding their role in susceptibility and pathogenesis ( 17 , 23 , 32 ). Studies in a Mexican mestizo cohort found that the rs2304206 gene variant associated with increased IRF3 expression in plasmacytoid dendritic cells (pDCs), with elevated type I IFN expression and dsDNA autoantibodies ( 32 ).…”

Section: Implications For Irfs In Disease Pathogenesis–why Target Thementioning

confidence: 99%

“…Indeed, hyper-activation of IRFs (most notably IRF1, IRF3, IRF5, IRF7, and IRF9) has been implicated in disease pathogenesis as it leads to unrestricted production of IFNs, which is linked to the development of numerous inflammatory and autoimmune diseases ( 17 , 18 ). Further, polymorphisms in IRF genes show either protection from or increased susceptibility to the development of such diseases ( 19 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

2018

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The interferon regulatory factors (IRFs) are a family of master transcription factors that regulate pathogen-induced innate and acquired immune responses. Aberration(s) in IRF signaling pathways due to infection, genetic predisposition and/or mutation, which can lead to increased expression of type I interferon (IFN) genes, IFN-stimulated genes (ISGs), and other pro-inflammatory cytokines/chemokines, has been linked to the development of numerous diseases, including (but not limited to) autoimmune and cancer. What is currently lacking in the field is an understanding of how best to therapeutically target these transcription factors. Many IRFs are regulated by post-translational modifications downstream of pattern recognition receptors (PRRs) and some of these modifications lead to activation or inhibition. We and others have been able to utilize structural features of the IRFs in order to generate dominant negative mutants that inhibit function. Here, we will review potential therapeutic strategies for targeting all IRFs by using IRF5 as a candidate targeting molecule.

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Section: Implications For Irfs In Disease Pathogenesis–why Target Thementioning

confidence: 99%

Section: Implications For Irfs In Disease Pathogenesis–why Target Thementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

2018

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“…Several interferon regulatory factors (IRFs) have been implicated in autoimmunity 12 , 13 . Amongst the IRFs, IRF4 plays a fundamental role in T and B cells including IL-21 production, class switching, and PC differentiation 12 , 13 . The multifaceted role of IRF4 has been ascribed to its capacity to cooperate with multiple transactivators like the AP-1 family members, BATF and Jun, and the Ets protein PU.1 (ref.…”

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confidence: 99%

Regulation of age-associated B cells by IRF5 in systemic autoimmunity

et al. 2018

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Age-associated B cells (ABCs) are a T-bet–dependent B cell subset, which accumulates prematurely in autoimmune settings. The pathways regulating ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that controls both cytoskeletal dynamics and IRF4 activity. Notably, DEF6 is a newly identified human SLE-risk variant. Here we show that the lupus syndrome that developed in SWEF-deficient mice is accompanied by the accumulation of ABCs, which produce autoantibodies upon stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment in motifs bound by transcription factors of the IRF family, AP-1/BATF, and T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by interleukin 21 (IL-21) and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated IRF5 activity in response to IL-21 stimulation. These studies thus uncover a new genetic pathway controlling ABCs in autoimmunity.

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“…Authors highlighted that vast majority of studies, which supported the dual protective and adverse role in the susceptibility to development of autoimmune disorders, were conducted on irf-deficient mice models in vivo. Now, primarily researchers should pay attention to the role of impaired IRF system in patients' immune cell activity, especially in autoimmune diabetes [23]. There are no works confirming the occurrence of IRF4-IRF5 axis dysregulation in monocytederived cells in DM1 juveniles.…”

Section: Introductionmentioning

confidence: 99%

Monocytes of newly diagnosed juvenile DM1 patients are prone to differentiate into regulatory IL-10+ M2 macrophages

et al. 2019

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Alternatively activated macrophages (M2) exert anti-inflammatory effects and are crucial for keeping balance between protective and destructive cell-mediated immunity in healing phase of inflammation. Two members of the interferon regulatory factors family, IRF5 and IRF4, are known to promote M1 or M2 phenotype, respectively. Our study aimed to analyse the effectiveness of the M2 differentiation process in vitro (achieved by IL-4 stimulation) and its relationship to the stage of type 1 diabetes mellitus (DM1) in juvenile patients. To identify the basic changes in M2 phenotype, we examined the expression of the surface CD206, CD14, CD86 molecules, intracellular IRF4 and IRF5 transcription factors as well as IL-10 and TNFα intracellular production. Ten newly diagnosed (ND-DM1) and ten long-standing (LS-DM1) patients were enrolled into the study. The control group consisted of six children. We observed a significantly higher number of unpolarised CD206 + CD14 + cells in the M2 cultures of DM1 subjects when compared to healthy ones. Examined cells presented common features with M1 macrophages (high levels of the CD14/CD86/IRF5 markers); however, they were weak TNFα producers in ND-DM1 patients. For the first time, we have revealed dysregulated IRF4/IRF5 axis in the analysed subpopulation derived from diabetic patients. Additionally, monocytes of ND-DM1 children were still able to differentiate into regulatory IL-10 + M2 macrophages, while this process was highly limited in LS-DM1 patients. Summarising, we suggest that the M2 polarisation process is less effective in DM1 patients than in healthy subjects and it may vary depending on the stage of disease. It can be concluded that in vitro differentiated M2 macrophages may be used in the future as inflammatory inhibitors for adoptive therapy experiments in ND-DM1 subjects.

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Interferon regulatory factor signaling in autoimmune disease

Cited by 30 publications

References 166 publications

Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

Regulation of age-associated B cells by IRF5 in systemic autoimmunity

Monocytes of newly diagnosed juvenile DM1 patients are prone to differentiate into regulatory IL-10+ M2 macrophages

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