慢性阻塞性肺疾病（COPD）构成了显着的健康威胁，其特征是主要由肺单核细胞触发的肺部炎症。尽管炎症在COPD中的中心地位,管理这种反应的监管机制仍然难以捉摸，提出了抗炎干预的挑战。在这项研究中,我们评估了exportins在COPD小鼠模型中的表达，揭示小鼠肺中XPO6的显著上调(P=0.0011)。有趣的是，我们观察到来自人和小鼠COPD受试者的肺单核细胞中XPO6的一致上调(P<0.0001)。此外，在人类肺组织中，XPO6表达与TLR2表达呈正相关(P=0)。体外研究表明，XPO6增强TLR2表达，激活MyD88/NF-κB炎症信号通路。这种激活,反过来,促进促炎细胞因子如TNFα的分泌，单核细胞中的IL-6和IL-1β。机械上,XPO6促进TLR2mRNA的核输出，确保其稳定性和随后在单核细胞中的蛋白质表达。总之,我们的发现揭示了COPD肺单核细胞中XPO6的上调通过促进TLR2mRNA的核输出激活MyD88/NF-κB炎症信号通路,从而确定XPO6是COPD抗炎干预的有希望的治疗靶点。
Chronic obstructive pulmonary disease (COPD) poses a significant health threat characterized by lung inflammation primarily triggered by pulmonary monocytes. Despite the centrality of inflammation in COPD, the regulatory mechanisms governing this response remain elusive, presenting a challenge for anti-inflammatory interventions. In this study, we assessed the expression of exportins in COPD mouse models, revealing a notable upregulation of XPO6 in the mouse lung (P = 0.0011). Intriguingly, we observed a consistent upregulation of XPO6 in pulmonary monocytes from both human and mouse COPD subjects (P < 0.0001). Furthermore, in human lung tissue, XPO6 expression exhibited a positive correlation with TLR2 expression (P = 0). In vitro investigations demonstrated that XPO6 enhances TLR2 expression, activating the MyD88/NF-κB inflammatory signaling pathway. This activation, in turn, promotes the secretion of pro-inflammatory cytokines such as TNFα, IL-6, and IL-1β in monocytes. Mechanistically, XPO6 facilitates the nuclear export of TLR2 mRNA, ensuring its stability and subsequent protein expression in monocytes. In conclusion, our findings unveil that the upregulation of XPO6 in COPD pulmonary monocytes activates the MyD88/NF-κB inflammatory signaling pathway by facilitating the nuclear export of TLR2 mRNA, thereby identifying XPO6 as a promising therapeutic target for anti-inflammatory interventions in COPD.
