# RNA-binding protein tristetraprolin inhibits Th2 cell activation and differentiation in allergic rhinitis by promoting TRIM18 mRNA decay

## TL;DR

The RNA-binding protein TTP reduces Th2 cell activity and nasal inflammation in allergic rhinitis by breaking down TRIM18 mRNA.

## Contribution

This study reveals a novel mechanism by which TTP inhibits Th2 cell differentiation through TRIM18 mRNA destabilization in allergic rhinitis.

## Key findings

- TTP overexpression in AR mice reduced nasal inflammation and Th2 cytokine levels.
- TTP binds to TRIM18 mRNA's 3′UTR, decreasing its stability via a Cys-139-dependent mechanism.
- TRIM18 overexpression counteracts TTP's inhibitory effects on Th2 cell activation.

## Abstract

Tristetraprolin (TTP), which encodes an RNA-binding protein, was identified as a biomarker in three types of IgE-driven allergic tissues. Remarkably, in the nasal mucosa of the ragweed pollen-induced AR mouse model, TTP mRNA levels were increased approximately threefold. TTP overexpression in AR mice alleviated nasal inflammation and epithelial barrier damage, accompanied by reduced frequency of nasal spray and nasal friction, eosinophils/neutrophils/macrophages/goblet cells infiltration, and Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 secretion. The impact of TTP on the activation and differentiation of Th2 cells was assessed by utilizing naïve CD4 T cells isolated from mice. We found that TTP significantly suppressed Th2 activation and differentiation, as evidenced by the decreased levels of cytokines and the percentage of Th2. Transcriptomic profiling of CD4+ T cells (with/without TTP overexpression) was analyzed, and 14 down-regulated genes containing AU-rich elements (AREs) were obtained. The study concentrated on downregulated E3 ubiquitin ligase tripartite motif 18 (TRIM18) in TTP-overexpressed CD4+ T cells. Specifically, TTP protein bound to the ARE located at positions +3640 to +3644 (5′-UAUUU-3′) within the 3′UTR of mouse TRIM18, and this interaction reduces TRIM18 mRNA stability, a process that depends on the active-site residue Cys-139 within the second CCCH-type zinc finger motif of TTP. TRIM18 overexpression weakened the effects in CD4+ T cells induced by TTP overexpression. Collectively, TTP suppresses Th2 activation and differentiation in AR by modulating TRIM18 mRNA stability, highlighting their interaction as a critical pathway in allergic inflammation.