Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Toxicol Lett. 2021 Jan 1;336:57-67. doi: 10.1016/j.toxlet.2020.10.002. Epub 2020 Oct 16.
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.
作为职业性哮喘的主要病因之一，甲苯二异氰酸酯（TDI）诱导的哮喘是一种气道炎症性疾病，其最显著的特征之一是炎症，其中晚期糖基化终产物受体（RAGE）起着极其重要的作用。然而，RAGE 上调的机制尚不清楚。本研究旨在探讨 JNK 是否通过激活 RAGE 介导β-连环蛋白的稳定来调节哮喘。在此，通过分析健康供体和哮喘患者的血液，发现 RAGE 和 p-JNK 的表达高度相关，并且与支气管哮喘的严重程度呈正相关。此外，通过用 TDI 致敏和攻击小鼠，我们发现 RAGE 抑制剂（FPS-ZM1）和 JNK 抑制剂（SP600125）显著减轻了体内 TDI 诱导的哮喘炎症。此外，SP600125 还显著恢复了 RAGE 和 p-JNK 的表达。此外，在 TDI-HSA 处理 16HBE 细胞的体外实验中发现，JNK 的治疗性抑制可降低 TDI 驱动的 RAGE 表达和β-连环蛋白易位，而 JNK 激动剂 Anisomycin 的处理则表现出相反的效果。此外，RAGE 的基因敲低不会导致 JNK 磷酸化，表明 JNK 位于 RAGE 上游发挥作用。综上所述，这些发现强调了 JNK 信号在 RAGE/β-连环蛋白调节中的作用，并对 TDI 诱导的哮喘的治疗具有重要的治疗意义。
