Tristetraprolin-mediated mRNA destabilization regulates basophil inflammatory responses.

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.