BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea.
Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Korea.
Molecules. 2021 Sep 6;26(17):5409. doi: 10.3390/molecules26175409.
Primary cilia mediate the interactions between cells and external stresses. Thus, dysregulation of primary cilia is implicated in various ciliopathies, e.g., degeneration of the retina caused by dysregulation of the photoreceptor primary cilium. Particulate matter (PM) can cause epithelium injury and endothelial dysfunction by increasing oxidative stress and inflammatory responses. Previously, we showed that PM disrupts the formation of primary cilia in retinal pigment epithelium (RPE) cells. In the present study, we identified 2-isopropylmalic acid (2-IPMA) as a novel inducer of primary ciliogenesis from a metabolite library screening. Both ciliated cells and primary cilium length were increased in 2-IPMA-treated RPE cells. Notably, 2-IPMA strongly promoted primary ciliogenesis and restored PM2.5-induced dysgenesis of primary cilia in RPE cells. Both excessive reactive oxygen species (ROS) generation and activation of a stress kinase, JNK, by PM2.5 were reduced by 2-IPMA. Moreover, 2-IPMA inhibited proinflammatory cytokine production, i.e., IL-6 and TNF-α, induced by PM2.5 in RPE cells. Taken together, our data suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in RPE cells.
初级纤毛介导细胞与外部应激之间的相互作用。因此，初级纤毛的调节异常与各种纤毛病有关，例如感光器初级纤毛调节异常导致的视网膜变性。颗粒物 (PM) 可通过增加氧化应激和炎症反应引起上皮损伤和血管内皮功能障碍。先前，我们表明 PM 会破坏视网膜色素上皮 (RPE) 细胞中初级纤毛的形成。在本研究中，我们从代谢物文库筛选中鉴定出 2-异丙基苹果酸 (2-IPMA) 是一种新的初级纤毛发生诱导剂。2-IPMA 处理的 RPE 细胞中，有纤毛的细胞和初级纤毛长度都增加了。值得注意的是，2-IPMA 强烈促进了初级纤毛的发生，并恢复了 PM2.5 诱导的 RPE 细胞中初级纤毛的发育不良。PM2.5 引起的过量活性氧 (ROS) 生成和应激激酶 JNK 的激活均被 2-IPMA 降低。此外，2-IPMA 抑制了 PM2.5 在 RPE 细胞中诱导的促炎细胞因子，即白细胞介素 6 (IL-6) 和肿瘤坏死因子-α (TNF-α) 的产生。综上所述，我们的数据表明 2-IPMA 通过促进 RPE 细胞中的初级纤毛发生来改善 PM2.5 诱导的炎症。
