A recent investigation has highlighted the crucial function of tristetraprolin (TTP), an RNA-binding protein, in managing inflammatory reactions in basophils—immune cells that play a fundamental role in allergy responses. The findings indicate that TTP is responsible for maintaining the stability of mRNAs that encode inflammatory substances, thereby curbing their excessive production. By using mice lacking TTP, researchers observed an increase in allergic inflammation, indicating that TTP could be a valuable target for therapies aimed at allergic and inflammatory diseases.
A recent investigation conducted by scientists at the Institute of Science Tokyo has highlighted the crucial function of tristetraprolin (TTP), an RNA-binding protein, in managing inflammatory reactions in basophils—immune cells that play a fundamental role in allergy responses. The findings indicate that TTP is responsible for maintaining the stability of mRNAs that encode inflammatory substances, thereby curbing their excessive production. By utilizing TTP-deficient mice, the researchers observed an increase in allergic inflammation, suggesting that TTP may serve as a valuable target for therapies aimed at allergic and inflammatory diseases.
Inflammation is an essential aspect of the body’s defense system, essential for combating infections and healing tissue injuries. Basophils, which constitute less than 1% of white blood cells, have recently been recognized as significant contributors to allergic responses through the release of pro-inflammatory cytokines like IL-4. Although the involvement of basophils in inflammation is well-documented, the underlying molecular processes that regulate their production of cytokines have not been fully understood.
To fill this knowledge gap, researchers from the Institute of Science Tokyo, led by Professor Kensuke Miyake, investigated the role of tristetraprolin (TTP) in managing inflammatory responses in basophils. The outcomes of this study were published in Allergology International on November 15, 2024. The research reveals that TTP facilitates the degradation of mRNAs that code for inflammatory cytokines and chemokines, thus regulating the inflammatory responses of basophils. Although TTP’s function in other immune cells has been explored, its specific role in basophils has received limited attention, making this study vital for potential therapeutic applications in allergic and inflammatory diseases.
Miyake elaborates, “Our study utilized wild-type and TTP-knockout mice to delve into TTP’s function in basophils. We stimulated basophils from each group with antigens combined with IgE, IL-33, or lipopolysaccharide (LPS). We then assessed gene expression, mRNA stability, and levels of inflammatory proteins. To analyze these processes comprehensively, we used RNA sequencing (RNA-seq) to evaluate global gene expression and SLAM-seq to study mRNA stability. Additionally, to gain further insights into TTP’s in vivo roles, we created basophil-specific TTP-knockout mice and examined the severity of allergic inflammation utilizing an oxazolone-induced atopic dermatitis model.”
The findings demonstrated that TTP is crucial in controlling the production of inflammatory substances in basophils. After activation, TTP expression increased significantly in basophils exposed to antigen/IgE, IL-33, and LPS. In basophils lacking TTP, mRNAs for vital inflammatory molecules such as Il4, Il13, Areg, Ccl3, Cxcl2, and Ptgs2 experienced prolonged stability, which resulted in excessive production of cytokines and chemokines. To further evaluate TTP’s function in basophils in vivo, the researchers deployed basophil-specific TTP-deficient mice (genetically modified to lack TTP only in basophils). In a skin allergy model, these mice displayed heightened allergic inflammation, indicated by greater ear swelling and more prominent skin scaling and hardening.
Miyake comments, “TTP mitigates the overproduction of inflammatory molecules by promoting the degradation of their mRNA. Without TTP, mRNAs remain stable for extended periods, resulting in excessive cytokine production and intensified allergic reactions.” This research highlights TTP as a significant regulator of inflammatory responses in basophils and suggests that targeting TTP or its pathways could lead to innovative treatment strategies for allergic diseases like asthma and atopic dermatitis.
In summary, this research offers essential insights into the regulatory role of TTP in allergic inflammation, potentially paving the way for the creation of targeted therapies for allergic disorders, which may lead to more accurate treatments and better patient outcomes.
