Abstract：
Asthma is a prevalent chronic respiratory disease, yet understanding its ecology and pathogenesis remains a challenge. Trim27, a ubiquitination ligase belonging to the TRIM (tripartite motif-containing) family, has been implicated in regulating multiple pathophysiological processes such as inflammation, oxidative stress, apoptosis, and cell proliferation. However, the role of Trim27 in asthma has not been investigated. Our study found that Trim27 expression significantly increases in the airway epithelium of asthmatic mice. Knockdown of Trim27 expression effectively relieved ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and lung tissue histopathological changes. Moreover, Trim27 knockdown exhibited a significant reduction in airway inflammation and oxidative stress in asthmatic mice, and in vitro analysis confirmed the favorable effect of Trim27 deletion on inflammation and oxidative stress in mouse airway epithelial cells. Furthermore, our study revealed that deletion of Trim27 in MLE12 cells significantly decreased NLRP3 inflammasome activation, as evidenced by reduced expression of NLRP3, ASC, and pro-IL-1β mRNA. This downregulation was reversed when Trim27, but not its mutant lacking ubiquitination ligase activity, was replenished in these cells. Consistent with these findings, protein levels of NLRP3, pro-caspase-1, pro-IL-1β, cleaved-caspase-1, and cleaved-IL-1β were higher in Trim27-replenished cells compared to cells expressing Trim27C/A. Functionally, the downregulation of IL-1β and IL-18 levels induced by Trim27 deletion was rescued by replenishing Trim27. Overall, our findings provide evidence that Trim27 contributes to airway inflammation and oxidative stress in asthmatic mice via NLRP3 inflammasome activation, providing crucial insights into potential therapeutic interventions targeting Trim27 as a way to treat asthma.
摘要：
哮喘是一种常见的慢性呼吸道疾病,然而，了解其生态学和发病机制仍然是一个挑战。Trim27，属于TRIM（含三方基序）家族的泛素化连接酶，参与调节多种病理生理过程，如炎症，氧化应激，凋亡，和细胞增殖。然而,Trim27在哮喘中的作用尚未得到研究.我们的研究发现Trim27在哮喘小鼠气道上皮中的表达显着增加。敲除Trim27表达可有效缓解卵清蛋白（OVA）诱导的气道高反应性（AHR）和肺组织病理改变。此外，Trim27敲低显示哮喘小鼠气道炎症和氧化应激的显著降低，和体外分析证实了Trim27缺失对小鼠气道上皮细胞炎症和氧化应激的有利作用。此外，我们的研究表明，MLE12细胞中Trim27的缺失显著降低了NLRP3炎性体的激活，如NLRP3、ASC、和pro-IL-1βmRNA。当Trim27，而不是其缺乏泛素化连接酶活性的突变体时，这种下调被逆转，在这些细胞中补充。与这些发现一致，NLRP3，caspase-1，IL-1β蛋白水平，与表达Trim27C/A的细胞相比，补充Trim27的细胞中裂解的caspase-1和裂解的IL-1β更高。功能上,补充Trim27可以挽救Trim27缺失引起的IL-1β和IL-18水平的下调。总的来说,我们的发现提供证据表明Trim27通过NLRP3炎症小体激活促进哮喘小鼠的气道炎症和氧化应激,为以Trim27为治疗哮喘的潜在治疗干预提供重要见解.
