抑制 DNMT1 可减轻实验性食物过敏。

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology Pub Date : 2024-07-26 DOI:10.1016/j.molimm.2024.07.009

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引用次数: 0

摘要

背景：食物过敏（FA）的治疗需要改进。通过调节表观遗传标记可以改善免疫紊乱的治疗，这是一种很有前景的方法。本研究的目的是通过使用 DNA 甲基转移酶-1（DNMT1）抑制剂来缓解实验性 FA：方法：使用卵清蛋白作为特异性抗原建立小鼠 FA 模型。从FA小鼠体内分离出肠道IL-35+调节性B细胞（Breg细胞），并采用免疫学方法对其进行鉴定：结果：FA小鼠IL-35+ Breg细胞的频率较低，这与它们的FA反应成反比。FA小鼠肠道Breg细胞中IL-35的含量较低。在Il35启动子中检测到了高甲基化状态，并伴有高水平的H3K9me3。DNMT1 的强制表达阻碍了 IL35 基因启动子的活性。服用 DNMT1 抑制剂（RG108）可恢复 FA 肠 Bregs 的免疫调节能力，并有效抑制 DNMT1 的表达，减轻实验性 FA 的病情：结论：肠道Breg细胞中DNMT1数量的升高损害了IL-35的表达，影响了免疫调节功能，从而促进了FA的发生。抑制DNMT1可恢复肠道Breg细胞的免疫调节功能，并减轻实验性FA。

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Inhibition of DNMT1 attenuates experimental food allergy

Background

The treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1).

Methods

Ovalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35⁺ regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches.

Results

FA mice had a lower frequency of IL-35⁺ Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA.

Conclusions

The elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1.

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来源期刊

Molecular immunology 医学-免疫学

CiteScore

6.90

自引率

2.80%

发文量

324

审稿时长

50 days

期刊介绍： Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.