An AAAG-Rich Oligodeoxynucleotide Rescues Mice from Bacterial Septic Peritonitis by Interfering Interferon Regulatory Factor 5

Gao, Shuang; Li, Xin; Nie, Shu; Yang, Lei; Tu, Liqun; Dong, Boqi; Zhao, Peiyan; Wang, Yangyang; Yu, Yongli; Wang, Liying; Hua, Shucheng

doi:10.3390/ijms18051034

Cited by 12 publications

(15 citation statements)

References 33 publications

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“…The therapeutic possibilities with regard to modulation of IRF5 expression, its posttranslational modification, and/or functional interactions with its protein partners have been extensively discussed elsewhere (39,48). For example, AAAG-rich oligodeoxynucleotides that compete with IRF5 for the consensus DNA binding site in regulatory elements associated with inflammatory genes have been used successfully to ameliorate bacterial septic peritonitis and influenza-induced acute lung injury and to reduce the levels of IL-6, tumor necrosis factor, and type 2 nitric oxide synthase in mouse models (49,50).…”

Section: Discussionmentioning

confidence: 99%

Functional Genomic Analysis of a RUNX3 Polymorphism Associated With Ankylosing Spondylitis

Vecellio

Chen

Cohen

et al. 2021

Arthritis & Rheumatology

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Objective. To investigate the functional consequences of the single-nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter associated with susceptibility to ankylosing spondylitis (AS).Methods. Using nuclear extracts from Jurkat cells and primary human CD8+ T cells, the effects of rs4648889 on allele-specific transcription factor (TF) binding were investigated by DNA pull-down assay and quantitative mass spectrometry (qMS), with validation by electrophoretic mobility shift assay (EMSA), Western blotting of the pulleddown eluates, and chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction (qPCR) analysis. Further functional effects were tested by small interfering RNA knockdown of the gene for interferon regulatory factor 5 (IRF5), followed by reverse transcription-qPCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure the levels of IFNγ messenger RNA (mRNA) and protein, respectively.Results. In nuclear extracts from CD8+ T cells, results of qMS showed that relative TF binding to the AS-risk A allele of rs4648889 was increased 3.7-fold (P < 0.03) for Ikaros family zinc-finger protein 3 (IKZF3; Aiolos) and components of the NuRD complex, including chromodomain helicase DNA binding protein 4 (CHD4) (3.6-fold increase; P < 0.05) and retinoblastoma binding protein 4 (RBBP4) (4.1-fold increase; P < 0.03). In contrast, IRF5 bound significantly more to the AS-protective G allele compared to the AS-risk A allele (fold change 8.2; P = 0.003). Validation with Western blotting, EMSA, and ChIP-qPCR confirmed the differential allelic binding of IKZF3, CHD4, RBBP4, and IRF5. Silencing of IRF5 in CD8+ T cells increased the levels of IFNγ mRNA as measured by RT-qPCR (P = 0.03) and IFNγ protein as measured by ELISA (P = 0.02).Conclusion. These findings suggest that the association of rs4648889 with AS reflects allele-specific binding of this enhancer-like region to certain TFs, including IRF5, IKZF3, and members of the NuRD complex. IRF5 may have crucial influences on the functions of CD8+ lymphocytes, a finding that could reveal new therapeutic targets for the management of AS.

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Section: Discussionmentioning

confidence: 99%

Functional Genomic Analysis of a RUNX3 Polymorphism Associated With Ankylosing Spondylitis

Vecellio

Chen

Cohen

et al. 2021

Arthritis & Rheumatology

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“…Bioinformatics analysis revealed the mechanism of action of MS19 to be competition with IRF5 at regulatory consensus sequences in the promoter of target genes. MS19 was further studied in a murine model of septic peritonitis revealing that MS19 prolonged the survival of the mice and down-regulated the expression of iNOS, IRF5, IL6, and TNFα ( 135 ). Another interesting study using the natural polyphenol Mangiferin that is a component of Mangifera indica Linn.…”

Section: Current Therapeutic Strategies To Inhibit Irf5mentioning

confidence: 99%

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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“…There are rapidly emerging global health challenges in treatment against microbial infection owing to the development of resistance in microorganisms against many conventional antibiotics. , Even in developed countries, such as the United States, each year about 2 million people become infected with antibiotic resistant bacteria, resulting in at least 23 000 deaths annually. , It has been recently estimated that potentially 5 million deaths from sepsis cases occur worldwide each year as a result of antibiotic resistant infections, which is now recognized to be involved in the early activation of both pro- and anti-inflammatory responses. − In the past two decades, only oxazolidinones and cyclic lipopeptides reached the market, and they are limited due to only targeting Gram-positive bacteria . It is urgent to promote an effective antibacterial agent and to control bacterial resistance.…”

Section: Introductionmentioning

confidence: 99%

Slow-Release and Nontoxic Pickering Emulsion Platform for Antimicrobial Peptide

Cai

Cao

Regenstein

2020

J. Agric. Food Chem.

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The resistance in microorganisms against many conventional antibiotics has become a serious global health problem. However, antibacterial drug delivery materials are still limited in toxicity, short efficacy and reducing inflammation. The novel and natural Pickering emulsions stabilized by antimicrobial peptide nanoparticles were tested as promising platforms to control bacterial resistance development. The parasin I interacted or conjugated with lecithin or chitosan and formed nanoparticles encapsulated by Pickering emulsion. The protonation and deprotonation of amino groups in chitosan and parasin I resulted in nanoparticles in different aggregate states and changed emulsion stability. Moreover, the Pickering emulsion could induce severe bacterial agglomeration on both Gram-positive and Gram-negative bacteria than parasin I through the membrane disintegration mechanism. Furthermore, the Pickering emulsion could alleviate the cytotoxicity of human liver cells and hemolytic activity in rat blood cells. In combination with the lack of acute cytotoxicity in Kunming mice and milder, more effective anti-inflammatory effect in peritonitis demonstrated for these Pickering emulsions, especially chitosan peptide-embedded nanoparticles Pickering emulsion, a potential role in combating multidrug resistant bacteria in biomedical applications.

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An AAAG-Rich Oligodeoxynucleotide Rescues Mice from Bacterial Septic Peritonitis by Interfering Interferon Regulatory Factor 5

Cited by 12 publications

References 33 publications

Functional Genomic Analysis of a RUNX3 Polymorphism Associated With Ankylosing Spondylitis

Functional Genomic Analysis of a RUNX3 Polymorphism Associated With Ankylosing Spondylitis

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

Slow-Release and Nontoxic Pickering Emulsion Platform for Antimicrobial Peptide

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