Role of CC Chemokine Ligand 17 in Mouse Models of Chronic Obstructive Pulmonary Disease
Role of CC Chemokine Ligand 17 in Mouse Models of Chronic Obstructive Pulmonary Disease
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CC 趋化因子配体 17 在慢性阻塞性肺疾病小鼠模型中的作用
DOI：
10.1165/rcmb.2021-0069oc
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发表时间：
2022
影响因子：
6.4
通讯作者：
Shib
中科院分区：
文献类型：
--
作者：
Machida Hiroyoshi;Inoue Sumito;Igarashi Akira;Saitoh Shinichi;Yamauchi Keiko;Nishiwaki Michiko;Nemoto Takako;Otaki Yoichiro;Sato Masamichi;Sato Kento;Nakano Hiroshi;Yang Sujeong;Furuyama Kodai;Murano Hiroaki;Ishibashi Yu;Ota Takahito;Nakayama Takashi;Shib
肺功能恶化与慢性阻塞性肺疾病（COPD）患者预后不良显著相关。我们以前报道过CC趋化因子配体17/胸腺和活化调节趋化因子（CCL17/TARC）可能是COPD患者肺功能下降的预测因子。然而，CCL17在COPD发病机制中的作用尚不清楚。在这里，我们使用小鼠COPD模型研究了CCL17在肺部炎症中的作用。暴露于吸烟诱导CCL17的生产在支气管上皮细胞和肺泡巨噬细胞在肺中的积累。鼻内给予重组CCL17进一步增强香烟烟雾诱导的巨噬细胞积聚，并且还加重弹性蛋白酶诱导的肺气肿。我们证实，香烟烟雾（CS）提取物以及过氧化氢上调BAES-2B细胞中的CCL17。值得注意的是，M1和M2表面标志物的巨噬细胞均通过香烟烟雾蓄积。在CCL17缺陷小鼠中，通过暴露于吸烟和弹性蛋白酶给药诱导的肺气肿变化引起的肺泡巨噬细胞积聚均显著减少。我们进一步证明，CCL 17强烈诱导RAW264.7细胞中CC趋化因子配体2（CCL 2）（巨噬细胞的化学引诱物）的表达，并且其产生通过敲低CCL 17的受体CCR 4而受到抑制。总的来说，本结果表明，CCL17是由肺上皮细胞在CS暴露后产生的。此外，CCL17可能通过CCL17诱导的巨噬细胞产生CCL2参与CS诱导的肺泡巨噬细胞积聚和弹性蛋白酶诱导的肺气肿的发展。我们的发现可能为COPD的发病机制提供新的见解。
Lung function deterioration is significantly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). We previously reported that CC chemokine ligand 17/thymus and activation-regulated chemokine (CCL17/TARC) could be a predictive factor of lung function decline in patients with COPD. However, the role of CCL17 in the pathogenesis of COPD is unclear. Here we examined the role of CCL17 in lung inflammation using mouse COPD models. Exposure to cigarette smoking induced CCL17 production in bronchial epithelial cells and accumulation of alveolar macrophages in the lungs. Intranasal administration of recombinant CCL17 further enhanced cigarette smoke-induced macrophage accumulation and also aggravated elastase-induced pulmonary emphysema. We confirmed that cigarette smoke (CS) extract as well as hydrogen peroxide upregulated CCL17 in BAES-2B cells. Of note, macrophages of both M1 and M2 surface markers were accumulated by cigarette smoke. Both alveolar macrophage accumulation via exposure to cigarette smoking and emphysematous changes induced by elastase administration were significantly reduced in CCL17-deficient mice. We further demonstrated that CCL17 strongly induced the expression of CC chemokine ligand 2 (CCL2), a chemoattractant for macrophages, in RAW264.7 cells, and its production was inhibited by knockdown of CCR4, the receptor of CCL17. Collectively, the present results demonstrate that CCL17 is produced by lung epithelial cells upon CS exposure. Furthermore, CCL17 is involved in CS-induced accumulation of alveolar macrophages and development of elastase-induced pulmonary emphysema, possibly through CCL17-induced production of CCL2 by macrophages. Our findings may provide a new insight into the pathogenesis of COPD.