Targeting tristetraprolin in basophils: A breakthrough in allergic inflammation treatment

Inflammation is a crucial part of the body's defense mechanism, playing a key role in fighting infections and repairing tissue damage. Basophils, a type of immune cell that makes up less than 1% of white blood cells, have recently emerged as critical players in triggering allergic responses by releasing pro-inflammatory cytokines like IL-4. Despite the established role of basophils in inflammation, the molecular mechanisms controlling their cytokine production have remained unclear.

To address this gap, a group of researchers from Institute of Science Tokyo, led by Professor Kensuke Miyake, conducted a study to explore the role of tristetraprolin (TTP), an RNA-binding protein, in regulating inflammatory responses in basophils. Published in Allergology International on November 15, 2024, the study reveals that TTP promotes the degradation of mRNAs encoding inflammatory cytokines and chemokines, thereby controlling basophil inflammatory responses. While TTP's role in other immune cells has been studied, its specific function in basophils has not been fully explored, making this investigation crucial for its potential therapeutic implications for allergic and inflammatory conditions.

Miyake explains, "In this study, we used wild-type and TTP-knockout mice to explore the role of TTP in basophils. Basophils from each strain were stimulated with antigen combined with IgE, IL-33, or lipopolysaccharide (LPS). We measured gene expression, mRNA stability, and inflammatory protein levels. To analyze these processes at a transcriptome-wide scale, we employed RNA sequencing (RNA-seq) to assess global gene expression and SLAM-seq to examine mRNA stability. Furthermore, to gain deeper insights into TTP's roles in vivo, we established basophil-specific TTP-knockout mice and evaluated the severity of allergic inflammation using an oxazolone-induced atopic dermatitis model."

The study revealed that TTP plays a pivotal role in regulating the production of inflammatory mediators in basophils. Following stimulation, TTP expression was significantly upregulated in basophils with antigen/IgE, IL-33, and LPS. In TTP-deficient basophils, the stability of mRNAs encoding key inflammatory molecules, including Il4, Il13, Areg, Ccl3, Cxcl2, and Ptgs2, was prolonged, leading to excessive cytokine and chemokine production. To further assess the role of TTP in basophils in vivo, the researchers used basophil-specific TTP-deficient mice (genetically engineered mice lacking TTP exclusively in basophils). In a skin allergy model, these mice exhibited aggravated allergic inflammation, characterized by increased ear thickening with more pronounced skin scaling and hardening.

Miyake states, "By promoting the degradation of mRNA for inflammatory molecules, TTP prevents their overproduction. In the absence of TTP, mRNA remains stable for a longer period, leading to excessive cytokine production and exacerbated allergic responses." This research underscores TTP as a key regulator of inflammatory responses in basophils and suggests that targeting TTP or its pathways could lead to new strategies for treating allergic diseases like asthma and atopic dermatitis.

In summary, this study provides critical insights into how TTP regulates allergic inflammation. These findings could pave the way for the development of targeted therapies for allergic conditions, potentially offering more precise treatments and improving patient outcomes.