Background

Asthmatic and allergic inflammation is mediated by T_H2 cytokines (IL-4, IL-5, and IL-13). Although we have learned much about how T_H2 cells are differentiated, the T_H2 checkpoint mechanisms remain elusive.

Objectives

In this study we investigate how monocyte chemotactic protein–induced protein 1 (MCPIP1; encoded by the Zc3h12a gene) regulates IL-5–producing T_H2 cell differentiation and T_H2-mediated inflammation.

Methods

The functions of Zc3h12a^−/− CD4 T cells were evaluated by checking the expression of T_H2 cytokines and transcription factors in vivo and in vitro. Allergic airway inflammation of Zc3h12a^−/− mice was examined with murine asthma models. In addition, antigen-specific CD4 T cells deficient in MCPIP1 were transferred to wild-type recipient mice, challenged with ovalbumin (OVA) or house dust mite (HDM), and accessed for T_H2 inflammation.

Results

Zc3h12a^−/− mice have spontaneous severe lung inflammation, with an increase in mainly IL-5– and IL-13–producing but not IL-4–producing T_H2 cells in the lung. Mechanistically, differentiation of IL-5–producing Zc3h12a^−/− T_H2 cells is mediated through Notch signaling and Gata3 independent of IL-4. Gata3 mRNA is stabilized in Zc3h12a^−/− T_H2 cells. MCPIP1 promotes Gata3 mRNA decay through the RNase domain. Furthermore, deletion of MCPIP1 in OVA- or HDM-specific T cells leads to significantly increased T_H2-mediated airway inflammation in OVA or HDM murine models of asthma.

Conclusions

Our study reveals that MCPIP1 regulates the development and function of IL-5–producing T_H2 cells through the Notch/Gata3 pathway. MCPIP1 represents a new and promising target for the treatment of asthma and other T_H2-mediated diseases.

中文翻译：

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单核细胞趋化蛋白诱导的蛋白1通过抑制通过Notch / Gata3途径产生IL-5的T _H 2细胞来控制过敏性气道炎症

背景

哮喘和过敏性炎症是由T _H 2细胞因子（IL-4，IL-5和IL-13）介导的。尽管我们已经了解了许多有关T _H 2细胞如何分化的知识，但是T _H 2检查点机制仍然难以捉摸。

目标

在这项研究中，我们研究了单核细胞趋化蛋白诱导的蛋白1（MCPIP1；由Zc3h12a基因编码）如何调节产生IL-5的T _H 2细胞分化和T _H 2介导的炎症。

方法

通过检测体内和体外T _H 2细胞因子的表达和转录因子来评估Zc3h12a ^-/- CD4 T细胞的功能。用鼠哮喘模型检查了Zc3h12a ^-/-小鼠的过敏性气道炎症。此外，将缺乏MCPIP1的抗原特异性CD4 T细胞转移至野生型受体小鼠，用卵清蛋白（OVA）或屋尘螨（HDM）攻击，并进行T _H 2炎症反应。

结果

Zc3h12a ^-/-小鼠具有自发性严重肺部炎症，肺中主要产生IL-5和IL-13的T _H 2细胞增加，但不增加。从机制上讲^，产生IL-5的Zc3h12a ^-/- T _H 2细胞的分化是通过Notch信号传导和独立于IL-4的Gata3介导的。Gata3 mRNA在Zc3h12a ^-/- T _H 2细胞中稳定。MCPIP1通过RNase域促进Gata3 mRNA的降解。此外，MCPIP1的缺失在OVA-或HDM特异性T细胞导致显著增加的T _ħ在哮喘的OVA或HDM鼠模型2介导的气道炎症。

结论

我们的研究表明，MCPIP1通过Notch / Gata3途径调节产生IL-5的T _H 2细胞的发育和功能。MCPIP1代表了治疗哮喘和其他T _H 2介导的疾病的新靶标。