Liang Hao, Zhang Fengrui, Wang Wen, Zhao Wei, Zhou Jiao, Feng Yuran, Wu Jing, Li Maojuan, Bai Xinyu, Zeng Zhong, Niu Junkun, Miao Yinglei
Kunming Medical University, Kunming, China.
Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
Front Pharmacol. 2022 Jul 4;13:893426. doi: 10.3389/fphar.2022.893426. eCollection 2022.
The overactivation of NLRP3 inflammasome in intestinal epithelial cells (IECs) is among the important reasons for severe inflammation in ulcerative colitis (UC). We found that heat shock transcription factor 2 (HSF2), which is highly expressed in UC, could inhibit the activation of NLRP3 inflammasome and reduce IL-1β in IECs, but the mechanisms were still not clear. It has been reported that HSP72 regulated by HSF2 can enhance the mitophagy mediated by Parkin. The number of damaged mitochondria and the mitochondrial derived ROS (mtROS) can be reduced by mitophagy, which means the activity of NLRP3 inflammasome is inhibited. Therefore, we speculate that HSF2 might regulate the activation of NLRP3 inflammasome of IECs in UC through the mitophagy mediated by Parkin. This study proves that the number of damaged mitochondria in IECs, the level of mitophagy, and the level of ROS in intestinal mucosa are positively correlated with the severity of UC. In mice and cells, mitophagy was promoted by HSF2 through the PARL/PINK1/Parkin pathway. This study reveals the potential mechanisms of HSF2 decreasing mtROS of IECs in UC.
肠道上皮细胞（IECs）中NLRP3炎性小体的过度激活是溃疡性结肠炎（UC）严重炎症的重要原因之一。我们发现，在UC中高表达的热休克转录因子2（HSF2）可抑制IECs中NLRP3炎性小体的激活并降低IL-1β水平，但其机制尚不清楚。据报道，由HSF2调控的HSP72可增强由Parkin介导的线粒体自噬。线粒体自噬可减少受损线粒体的数量以及线粒体衍生的活性氧（mtROS），这意味着NLRP3炎性小体的活性受到抑制。因此，我们推测HSF2可能通过Parkin介导的线粒体自噬来调节UC中IECs的NLRP3炎性小体的激活。本研究证明，IECs中受损线粒体的数量、线粒体自噬水平以及肠黏膜中ROS的水平与UC的严重程度呈正相关。在小鼠和细胞中，HSF2通过PARL/PINK1/Parkin途径促进线粒体自噬。本研究揭示了HSF2降低UC中IECs的mtROS的潜在机制。
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