Hamano Saaka, Matsumoto Koichiro, Tonai Ken, Fukuyama Satoru, Kan-O Keiko, Seki Nanae, Inoue Hiromasa, Nakanishi Yoichi
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, 812-8582 Japan.
Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
J Inflamm (Lond). 2017 Jan 17;14:2. doi: 10.1186/s12950-017-0149-4. eCollection 2017.
Airway viral infections cause the exacerbations of asthma and chronic obstructive pulmonary disease. PD-L1, also known as B7-H1, is an immune-checkpoint molecule that plays a role in an escape mechanism of viruses from the host immune systems. This escape may be associated with the persistence of viral infection and the exacerbation of the underlying diseases. In a study in vitro, we have shown that corticosteroids plus long-acting beta-agonists (LABAs) attenuate the upregulation of PD-L1 on airway epithelial cells stimulated with an analog of viral double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C). To address its biological relevance in vivo, we investigated the effect of corticosteroid plus LABA on the expression of PD-L1 in double-stranded RNA-induced lung inflammation in mice.
Mice were intratracheally administered with poly I:C. The expression of PD-L1 on the lung cells was assessed by flow cytometry and inflammation was assessed for bronchoalveolar lavage fluid (BALF). Independent as well as combination effects of ciclesonide and indacaterol were examined.
Administration of low dose poly I:C upregulated the expression of PD-L1, induced neutrophilia and increased keratinocyte-derived chemokine (KC), macrophage inflammatory protein-1β (MIP-1β), and IL-6 in BALF. The upregulation of PD-L1, neutrophilic inflammation and increase of KC were suppressed by ciclesonide plus indacaterol, but not by either when administered independently. Although the upregulation of PD-L1 by high dose poly I:C was suppressed by ciclesonide plus indacaterol, neutrophilia and increased KC, MIP-1β, and IL-6 in BALF were not attenuated.
Ciclesonide plus indacaterol attenuate double-stranded RNA-induced upregulation of PD-L1 in the lungs.
气道病毒感染会导致哮喘和慢性阻塞性肺疾病的加重。程序性死亡受体配体1（PD-L1），也称为B7-H1，是一种免疫检查点分子，在病毒逃避宿主免疫系统的机制中发挥作用。这种逃避可能与病毒感染的持续存在以及基础疾病的加重有关。在一项体外研究中，我们已经表明，皮质类固醇加长效β2受体激动剂（LABA）可减弱病毒双链RNA类似物聚肌苷酸-聚胞苷酸（poly I:C）刺激的气道上皮细胞上PD-L1的上调。为了探讨其在体内的生物学相关性，我们研究了皮质类固醇加LABA对双链RNA诱导的小鼠肺部炎症中PD-L1表达的影响。
小鼠经气管内给予poly I:C。通过流式细胞术评估肺细胞上PD-L1的表达，并对支气管肺泡灌洗液（BALF）进行炎症评估。研究了环索奈德和茚达特罗的单独作用以及联合作用。
低剂量poly I:C给药上调了PD-L1的表达，诱导了中性粒细胞增多，并增加了BALF中角质形成细胞衍生的趋化因子（KC）、巨噬细胞炎性蛋白-1β（MIP-1β）和白细胞介素-6。环索奈德加茚达特罗可抑制PD-L1的上调、中性粒细胞炎症以及KC的增加，但单独给药时均无此作用。虽然高剂量poly I:C引起的PD-L1上调被环索奈德加茚达特罗抑制，但BALF中的中性粒细胞增多以及KC、MIP-1β和白细胞介素-6的增加并未减弱。
环索奈德加茚达特罗可减弱双链RNA诱导的肺部PD-L1上调。
