Ko Jung Hwa, Yoon Sun-Ok, Lee Hyun Ju, Oh Joo Youn
Department of Ophthalmology, Seoul National University Hospital, 03080, Seoul, Korea.
Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 03080, Seoul, Korea.
Oncotarget. 2017 Jun 20;8(25):40817-40831. doi: 10.18632/oncotarget.17256.
Excessive and prolonged activation of macrophages underlies many inflammatory and autoimmune diseases. To regulate activation and maintain homeostasis, macrophages have multiple intrinsic mechanisms, one of which is modulation through autophagy. Here we demonstrate that autophagy induction by rapamycin suppressed the production of IL-1β and IL-18 in lipopolysaccharide- and adenosine triphosphate-activated macrophages at the post-transcriptional level by eliminating mitochondrial ROS (mtROS) and pro-IL1β in a p62/SQSTM1-dependent manner. In addition, rapamycin activated Nrf2 through up-regulation of p62/SQSTM1, which further contributed to the reduction of mtROS. Reduced IL-1β subsequently diminished the activation of p38 MAPK-NFκB pathways, leading to transcriptional down-regulation of IL-6, IL-8, MCP-1, and IκBα in rapamycin-treated macrophages. Therefore, our results suggest that rapamycin negatively regulates macrophage activation by restricting a feedback loop of NLRP3 inflammasome-p38 MAPK-NFκB pathways in autophagy- and p62/SQSTM1-dependent manners.
巨噬细胞的过度和持续激活是许多炎症和自身免疫性疾病的基础。为了调节激活并维持内环境稳定，巨噬细胞具有多种内在机制，其中之一是通过自噬进行调节。在此，我们证明雷帕霉素诱导的自噬通过以p62/SQSTM1依赖的方式消除线粒体ROS（mtROS）和前体IL-1β，在转录后水平抑制脂多糖和三磷酸腺苷激活的巨噬细胞中IL-1β和IL-18的产生。此外，雷帕霉素通过上调p62/SQSTM1激活Nrf2，这进一步有助于减少mtROS。减少的IL-1β随后减少了p38 MAPK-NFκB途径的激活，导致雷帕霉素处理的巨噬细胞中IL-6、IL-8、MCP-1和IκBα的转录下调。因此，我们的结果表明，雷帕霉素通过以自噬和p62/SQSTM1依赖的方式限制NLRP3炎性小体-p38 MAPK-NFκB途径的反馈环，对巨噬细胞激活产生负调节作用。
