To Bet or Not to Bet on T-bet As a Therapeutic Target in Emphysema?
To Bet or Not to Bet on T-bet As a Therapeutic Target in Emphysema?
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是否应该押注 T-bet 作为肺气肿的治疗目标？
DOI：
10.1165/rcmb.2019-0118ed
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发表时间：
2019
影响因子：
6.4
通讯作者：
Owen,CarolineA
中科院分区：
文献类型：
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作者：
Wang,Xiaoyun;Rojas-Quintero,Joselyn;Owen,CarolineA
在美国，慢性阻塞性肺疾病（COPD）影响2400万人，预计到2020年将成为全球第三大死亡原因（1）。COPD的主要病因危险因素是暴露于环境因子，特别是香烟烟雾（CS）。吸入CS或其他污染物会刺激慢性肺部炎症反应，其特征在于先天免疫细胞的过度募集和T辅助细胞1型（Th 1）型适应性免疫反应的激活（2）。T细胞中表达的T-box（T-bet或Tbx 21）是一种高度保守的转录因子，最初被鉴定为幼稚T淋巴细胞分化为Th 1细胞的主要调节因子（3）。T-bet还促进I组先天淋巴细胞（ILC 1）的活化，这是粘膜免疫的关键介质（4）。T-bet促进COPD患者肺部CD 4 + T细胞和ILC 1细胞产生IFN-γ和其他Th 1细胞因子（5）。T-betJ/J小鼠在肺中自发地形成异常表型，其特征在于向Th 2淋巴细胞的转变和哮喘的特征，包括对吸入的乙酰胆碱的支气管高反应性和慢性气道重塑（8）。在体外用CS处理的CD 4 + T细胞中，以及在COPD患者的肺中的CD 4 + T细胞和ILC 1细胞中，T-bet表达增加（9，10）。基于这些观察结果，人们可能期望T-betJ/J小鼠免受CS诱导的COPD的影响，但这一假设迄今尚未得到正式验证。在本期杂志中，Hayashi及其同事（pp. 525-536）报道，当用经肠内途径递送的猪胰弹性蛋白酶（PPE）攻击时，与野生型（WT）小鼠相比，T-betJ/J小鼠发展出加重的肺气肿（11）。PPE处理的T-betJ/J小鼠中夸大的肺气肿表型与增强的中性粒细胞和淋巴细胞进入其肺部的早期募集有关。尽管PPE处理的T-betJ/J小鼠的肺部CD 8 + T细胞计数与WT小鼠相似，但它们的肺部表达IL-17和RAR相关孤儿受体γ（RORgt）（Th 17细胞）的CD 4 + T细胞计数较高，IL-6和IL-17的表达增加。递送IL-6 R和IL-17的中和抗体改善了PPE处理的T-betJ/J小鼠中增加的肺气肿发展，表明T-betJ/J小鼠中过度的PPE诱导的肺气肿需要增加的IL-6和IL-17信号传导。然后，作者定位了肺中IL-6和IL-17的来源。与活化的WT巨噬细胞相比，离体活化的T-betJ/J巨噬细胞具有增加的IL-6表达。沉默小鼠肺泡上皮细胞中T-bet的表达
In the United States, chronic obstructive pulmonary disease (COPD) affects 24 million people, and it is projected to become the third leading cause of death worldwide by 2020 (1). The major etiologic risk factor for COPD is exposure to environmental agents, especially cigarette smoke (CS). Inhaling CS or other pollutants stimulates a chronic pulmonary inflammatory response that is characterized by excessive recruitment of innate immune cells and activation of a T-helper cell type 1 (Th1)-type adaptive immune response (2). T-box expressed in T cells (T-bet or Tbx21) is a highly conserved transcription factor that was initially identified as the master regulator of the differentiation of naive T lymphocytes into Th1 cells (3). T-bet also promotes the activation of group I innate lymphoid cells (ILC1), which are crucial mediators of mucosal immunity (4). T-bet promotes the production of IFN-g and other Th1 cytokines by CD4+ T cells and ILC1 cells in the lungs of patients with COPD (5). T-bet is also expressed by myeloid leukocytes (6, 7), but less is known about its contributions to their function.T-betJ/J mice spontaneously develop an abnormal phenotype in the lungs characterized by a shift toward Th2 lymphocytes and characteristics of asthma, including bronchial hyperresponsiveness to inhaled acetylcholine and chronic airway remodeling (8). T-bet expression is increased in CD4+ T cells treated with CS in vitro, and in CD4+ T cells and ILC1 cells in the lungs of patients with COPD (9, 10). Based on these observations, one might expect T-betJ/J mice to be protected from CS-induced COPD, but this hypothesis has not been formally tested until now. In this issue of the Journal, Hayashi and colleagues (pp. 525-536) report that when challenged with porcine pancreatic elastase (PPE) delivered by the intratracheal route, T-betJ/J mice developed exaggerated emphysema compared with wild-type (WT) mice (11). The exaggerated emphysema phenotype in the PPE-treated T-betJ/J mice was associated with enhanced early recruitment of neutrophils and lymphocytes into their lungs. Although the PPE-treated T-betJ/J mice had pulmonary CD8+ T cell counts similar to those obtained in the WT mice, they had higher counts of CD4+ T cells expressing Il-17 and RAR-related orphan receptor gamma (RORgt)(Th17 cells), and increased expression of Il-6 and Il-17 in their lungs. Delivering neutralizing antibodies to Il-6R and Il-17 ameliorated the increased emphysema development in the PPE-treated T-betJ/J mice, indicating that increased Il-6 and Il-17 signaling is required for the exaggerated PPE-induced emphysema in T-betJ/J mice. The authors then localized the sources of Il-6 and Il-17 in the lungs. T-betJ/J macrophages activated ex vivo had increased Il-6 expression compared with activated WT macrophages. Silencing T-bet expression in a murine alveolar