JNK modulates RAGE/β-catenin signaling and is essential for allergic airway inflammation in asthma. (1st January 2021)

• Record Type: Journal Article
• Authors: Huang, Guohua; Su, Jinwei; Zhao, Wenqu; Deng, Zhixuan; Wang, Ping; Dong, Hangming; Zhao, Haijin; Cai, Shaoxi
• Is Part Of: Toxicology letters. Volume 336(2021)
• Page Start: 57
• Page End: 67
• Publication Date: 2021-01-01
• Subjects: Allergic airway inflammation -- c-Jun NH2 terminal kinase -- Receptor of advanced glycation end products -- β-catenin distribution; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2020.10.002
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: The expression of RAGE and p-JNK is highly correlated and elevated concomitantly with the severity of bronchial asthma. RAGE inhibitor and JNK inhibitor reduced the TDI-induced asthma inflammation in vivo. The therapeutic inhibition of JNK reduced TDI driving RAGE expression and β-catenin translocation. The genetic knockdown of RAGE does not contribute to JNK phosphorylation, indicating that JNK functions upstream of RAGE. JNK signaling plays an important role in RAGE/β-catenin regulation and have important therapeutic implications for the treatment of TDI induced asthma. Abstract: As a leading cause of occupational asthma, toluene diisocyanate (TDI)-induced asthma is an inflammatory disease of the airways with one of the most significant characteristics involving inflammation, in which the receptor of advanced glycation end products (RAGE) plays an extremely important role. However, the mechanism underlying the upregulation of RAGE is still unknown. The aim of the present study was to examine whether JNK mediates β-catenin stabilization via activation of RAGE in asthma. Herein from the results by analyzing the blood from healthy donors and patients with asthma, it was found that the expression of RAGE and p-JNK is highly correlated and elevated concomitantly with the severity of bronchial asthma. Additionally, upon sensitizing and challenging the mice with TDI, we found that RAGE inhibitor (FPS-ZM1) and JNK inhibitor (SP600125) significantly reduced the TDI-induced asthma inflammation in vivo. Furthermore, SP600125 also considerably restored RAGE and p-JNK expression. Besides, the in vitro results from TDI-HSA treatment of 16HBE cells reveal that therapeutic inhibition of JNK reduced TDI driving RAGE expression and β-catenin translocation, while treatment with Anisomycin, a JNK agonist, showed the opposite effect. Moreover, genetic knockdown of RAGE does not contribute to JNK phosphorylation, indicating that JNK functions upstream of RAGE. Collectively, these findings highlight a role for JNK signaling in RAGE/β-catenin regulation and have important therapeutic implications for the treatment of TDI induced asthma.