Tristetraprolin-mediated mRNA destabilization regulates basophil inflammatory responses.

IF 6.2 2区医学 Q1 ALLERGY Allergology International Pub Date : 2024-11-15 DOI:10.1016/j.alit.2024.10.005

Junya Ito, Kensuke Miyake, Tomoki Chiba, Kazufusa Takahashi, Yutaro Uchida, Perry J Blackshear, Hiroshi Asahara, Hajime Karasuyama

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Abstract

Background: Basophils, despite being the least common granulocytes, play crucial roles in type 2 immune responses, such as chronic allergic inflammation and protective immunity against parasites. However, the molecular mechanisms regulating basophil activation and inflammatory molecule production remain poorly understood. Therefore, we investigated the role of RNA-binding proteins, specifically tristetraprolin (TTP), in regulating inflammatory molecule production in basophils.

Methods: Using antigen/IgE-stimulated basophils from wild-type (WT) and TTP-knockout (TTP-KO) mice, we performed bulk RNA sequencing, transcriptome-wide mRNA stability assays, and protein analyses. We also examined mRNA expression and protein production of inflammatory molecules in TTP-KO basophils under stimulation with IL-33 or LPS. Furthermore, we evaluated the in vivo significance of TTP in basophils using basophil-specific TTP-deficient mice and a hapten oxazolone-induced atopic dermatitis model.

Results: TTP expression was upregulated in basophils following stimulation with antigen/IgE, IL-33, or LPS. Under these stimuli, TTP-KO basophils exhibited elevated mRNA expression of inflammatory molecules, such as Il4, Areg, Ccl3, and Cxcl2, compared to WT basophils. Transcriptome-wide mRNA stability assays revealed that TTP deficiency prolonged the mRNA half-life of these inflammatory mediators. Notably, the production of these inflammatory proteins was significantly increased in TTP-KO basophils. Moreover, basophil-specific TTP-deficient mice showed exacerbated oxazolone-induced atopic dermatitis-like skin allergic inflammation.

Conclusions: TTP is a key regulator of basophil activation, controlling the production of inflammatory mediators through mRNA destabilization. Our in vivo findings demonstrate that the absence of TTP in basophils significantly aggravates allergic skin inflammation, highlighting its potential as a therapeutic target for allergic diseases.

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Tristetraprolin 介导的 mRNA 失稳调节了嗜碱性粒细胞的炎症反应。

背景：嗜碱性粒细胞是最不常见的粒细胞，但在慢性过敏性炎症和针对寄生虫的保护性免疫等第二类免疫反应中发挥着至关重要的作用。然而，人们对调节嗜碱性粒细胞活化和炎症分子产生的分子机制仍然知之甚少。因此，我们研究了 RNA 结合蛋白，特别是三萘普罗林（TTP）在调节嗜碱性粒细胞产生炎症分子中的作用：我们使用野生型（WT）小鼠和TTP基因敲除（TTP-KO）小鼠的抗原/IgE刺激的嗜碱性粒细胞，进行了大量RNA测序、全转录组mRNA稳定性检测和蛋白质分析。我们还检测了在 IL-33 或 LPS 刺激下 TTP-KO 嗜碱性粒细胞中炎症分子的 mRNA 表达和蛋白质生成情况。此外，我们还利用嗜碱性粒细胞特异性 TTP 缺失小鼠和草唑酮诱导的特应性皮炎模型评估了 TTP 在嗜碱性粒细胞中的体内意义：结果：在抗原/IgE、IL-33 或 LPS 的刺激下，嗜碱性粒细胞中的 TTP 表达上调。在这些刺激下，与 WT 嗜碱性粒细胞相比，TTP-KO 嗜碱性粒细胞表现出炎症分子（如 Il4、Areg、Ccl3 和 Cxcl2）mRNA 表达的升高。转录组 mRNA 稳定性检测显示，TTP 缺乏会延长这些炎症介质的 mRNA 半衰期。值得注意的是，TTP-KO 嗜碱性粒细胞中这些炎症蛋白的生成明显增加。此外，嗜碱性粒细胞特异性 TTP 缺陷小鼠表现出恶唑酮诱导的特应性皮炎样皮肤过敏炎症加剧：结论：TTP 是嗜碱性粒细胞活化的关键调节因子，通过破坏 mRNA 的稳定性来控制炎症介质的产生。我们的体内研究结果表明，嗜碱性粒细胞中 TTP 的缺失会显著加重皮肤过敏性炎症，这凸显了其作为过敏性疾病治疗靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Allergology International ALLERGY-IMMUNOLOGY

CiteScore

12.60

自引率

5.90%

发文量

审稿时长

29 weeks

期刊介绍： Allergology International is the official journal of the Japanese Society of Allergology and publishes original papers dealing with the etiology, diagnosis and treatment of allergic and related diseases. Papers may include the study of methods of controlling allergic reactions, human and animal models of hypersensitivity and other aspects of basic and applied clinical allergy in its broadest sense. The Journal aims to encourage the international exchange of results and encourages authors from all countries to submit papers in the following three categories: Original Articles, Review Articles, and Letters to the Editor.