Background

It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T_H2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T_H17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T_H2 and T_H17 cell differentiation and is mediated through nuclear factor κB activation. Ablation of TNF-α–induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor κB activation in myeloid cells and DCs, was shown to control DC activation.

Objective

In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of T_H2- and T_H17-cell mediated asthma.

Methods

We exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (by using the lysozyme M [LysM] promotor) or specifically in DCs (by using the Cd11c promotor) to acute and chronic house dust mite (HDM)–driven asthma models.

Results

We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3^CD11c or Tnfaip3^LysM mice dose-dependently controlled development of T_H17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely T_H2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific T_H17 cell differentiation through increased expression of the T_H17-instructing cytokines IL-1β, IL-6, and IL-23, whereas HDM-specific T_H2 cell differentiation was hampered by increased IL-12 and IL-6 production.

Conclusions

These data show that the extent of TNFAIP3 expression in DCs controls T_H2/T_H17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with T_H17-mediated neutrophilic inflammation.

中文翻译：

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TNF-α诱导的肺树突状细胞蛋白3水平指示嗜酸性或嗜中性哮喘中T _H 2或T _H 17细胞的分化

背景

目前尚不清楚为什么轻度至中度哮喘患者中的变应原暴露或环境触发会导致T _H 2介导的嗜酸性粒细胞炎症，而重度哮喘患者通常会出现T _H 17介导的嗜中性粒细胞炎症。树突状细胞（DCs）的激活状态对于T _H 2和T _H 17细胞分化均至关重要，并通过核因子κB激活介导。TNF-α诱导的蛋白3（TNFAIP3）的消融是髓样细胞和DC中核因子κB激活的关键负调控因子之一，被证明可以控制DC激活。

客观的

在这项研究中，我们调查了TNFAIP3在髓样细胞中对T _H 2和T _H 17细胞介导的哮喘发展的确切作用。

方法

我们将在骨髓细胞（通过使用溶菌酶M [LysM]启动子）或特在DC（通过使用Cd11c启动子）中有条件缺失Tnfaip3基因的小鼠暴露于急性和慢性室内尘螨（HDM）驱动的哮喘模型中。

结果

我们证明，无论是在Tnfaip3 ^CD11c还是Tnfaip3 ^LysM小鼠的DC中，Tnfaip3基因表达的降低在急性和慢性HDM驱动模型中均以剂量依赖性方式控制了T _H 17介导的嗜中性重度哮喘的发展，而野生型小鼠的纯T _H 2介导的嗜酸性炎症。缺乏TNFAIP3的DC通过增加指示T _H 17的细胞因子IL-1β，IL-6和IL-23的表达来诱导HDM特异性T _H 17细胞的分化，而HDM特异性T _H 2细胞的分化则受到增加的阻碍。 IL-12和IL-6的产生。

结论

这些数据表明，DC中TNFAIP3的表达程度控制着T _H 2 / T _H 17细胞的分化。这意味着减少DC活化可能是治疗患有T _H 17介导的嗜中性粒细胞炎症的重度哮喘患者的新药理干预措施。