RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model

BMC Pulmonary Medicine

Xiaohua Wang¹  Haijin Zhao¹  Yafei Yuan¹  Xianru Peng¹  Changhui Yu¹  Laiyu Liu¹  Bohou Li¹  Hangming Dong¹  Zihan Lan¹  Wenqu Zhao¹  Shaoxi Cai¹  Minyu Huang¹ 

[1] Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China;

关键词: Toluene diisocyanate (TDI);    Asthma;    Histone deacetylase 1 (HDAC1);    Receptor for advanced glycation end products (RAGE);   

DOI  :  10.1186/s12890-022-01832-3

来源: Springer

【 摘 要 】

BackgroundExposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model.MethodsBALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments.ResultsIn TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and β-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression.ConclusionsThese findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.

【 授权许可】

CC BY