Ito Junya, Miyake Kensuke, Chiba Tomoki, Takahashi Kazufusa, Uchida Yutaro, Blackshear Perry J, Asahara Hiroshi, Karasuyama Hajime
Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan; Department of Systems BioMedicine, Institute of Science Tokyo, Tokyo, Japan.
Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan.
Allergol Int. 2025 Apr;74(2):263-273. doi: 10.1016/j.alit.2024.10.005. Epub 2024 Nov 15.
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.
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.
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.
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.
嗜碱性粒细胞虽是最不常见的粒细胞，但在2型免疫反应中发挥着关键作用，如慢性过敏性炎症和针对寄生虫的保护性免疫。然而，调节嗜碱性粒细胞活化和炎症分子产生的分子机制仍知之甚少。因此，我们研究了RNA结合蛋白，特别是锌指蛋白36（TTP）在调节嗜碱性粒细胞炎症分子产生中的作用。
我们使用来自野生型（WT）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稳定性测定和蛋白质分析。我们还检测了TTP-KO嗜碱性粒细胞在IL-33或LPS刺激下炎症分子的mRNA表达和蛋白质产生。此外，我们使用嗜碱性粒细胞特异性TTP缺陷小鼠和半抗原恶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。
在用抗原/IgE、IL-33或LPS刺激后，嗜碱性粒细胞中TTP的表达上调。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的mRNA表达升高。全转录组mRNA稳定性测定表明，TTP缺陷延长了这些炎症介质的mRNA半衰期。值得注意的是，这些炎症蛋白的产生在TTP-KO嗜碱性粒细胞中显著增加。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性炎症加剧。
TTP是嗜碱性粒细胞活化的关键调节因子，通过使mRNA不稳定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的缺失显著加重过敏性皮肤炎症，突出了其作为过敏性疾病治疗靶点的潜力。
