1 Department of Respiratory and Critical Care Medicine and Nanfang Hospital, Southern Medical University , Guangzhou, China .
2 Department of General Medicine, Panyu Central Hospital , Guangzhou, China .
Antioxid Redox Signal. 2019 Feb 1;30(4):520-541. doi: 10.1089/ars.2017.7261. Epub 2018 May 7.
The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is activated by reactive oxygen species (ROS) and repressed by autophagy, has been identified as a novel agent of pulmonary fibrosis. Angiotensin II (AngII), the bioactive pro-oxidant in the renin-angiotensin system, aggravates lung fibrosis. However, the effect of AngII on NLRP3 inflammasome and autophagy in lung fibrosis remains unknown. This study investigates the potential link between AngII-induced autophagy in the regulation of NLRP3 inflammasome/IL-1β axis in lung fibrosis.
In vivo, autophagy and the NLRP3 inflammasome were activated in fibrotic patients and positively correlated with oxidation. Treatment with rapamycin promoted autophagy but inhibited oxidation, NLRP3 inflammasome, and lung fibrosis after bleomycin (BLM) infusion. The autophagy inhibitor 3-methyladenine reduced BLM-induced lung fibrosis and concurrently facilitated NLRP3 inflammasome activation and oxidation in fibroblasts. In vitro, AngII promoted intercellular ROS, hydrogen peroxide, and NADPH oxidase 4 (NOX4) protein levels and reduced the glutathione concentration, thereby leading to NLRP3 inflammasome activation and consequent collagen synthesis. AngII induced autophagy, while VAS2870, NOX4, small-interfering RNA (siRNA), and compound C eliminated AngII-induced LC3B augmentation. Moreover, blocking autophagy with bafilomycin A1 or LC3B siRNA resulted in oxidant accumulation, NLRP3 inflammasome hyperactivation, and collagen deposition. Finally, AngII induced P62/SQSTM1, targeting ubiquitinated apoptosis-associated speck-like protein containing a CARD for degradation, thereby contributing to NLRP3 inflammasome inactivation. Innovation and Conclusion: Autophagy attenuates pulmonary fibrosis by regulating NLRP3 inflammasome activation induced by AngII-mediated ROS via redox balance modulation.
NOD 样受体家族含 pyrin 域蛋白 3（NLRP3）炎性小体，可被活性氧（ROS）激活，被自噬抑制，已被确定为肺纤维化的一种新型介质。血管紧张素 II（AngII）是肾素-血管紧张素系统中的生物活性促氧化剂，可加重肺纤维化。然而，AngII 对肺纤维化中 NLRP3 炎性小体和自噬的影响尚不清楚。本研究探讨了 AngII 诱导的自噬在调节肺纤维化中 NLRP3 炎性小体/IL-1β 轴中的潜在联系。
在体内，纤维化患者的自噬和 NLRP3 炎性小体被激活，并且与氧化作用呈正相关。博来霉素（BLM）输注后，雷帕霉素处理可促进自噬，但抑制氧化、NLRP3 炎性小体和肺纤维化。自噬抑制剂 3-甲基腺嘌呤（3-methyladenine）可减少 BLM 诱导的肺纤维化，并同时促进成纤维细胞中 NLRP3 炎性小体的激活和氧化作用。在体外，AngII 可促进细胞间 ROS、过氧化氢和 NADPH 氧化酶 4（NOX4）蛋白水平升高，降低谷胱甘肽浓度，从而导致 NLRP3 炎性小体激活和随后的胶原合成。AngII 诱导自噬，而 VAS2870、NOX4、小干扰 RNA（siRNA）和化合物 C 则消除了 AngII 诱导的 LC3B 增加。此外，用巴弗洛霉素 A1 或 LC3B siRNA 阻断自噬会导致氧化剂积聚、NLRP3 炎性小体过度激活和胶原沉积。最后，AngII 诱导 P62/SQSTM1，即含有 CARD 用于降解的泛素化凋亡相关斑点样蛋白，从而有助于 NLRP3 炎性小体失活。
自噬通过调节 AngII 介导的 ROS 诱导的 NLRP3 炎性小体激活，从而减轻氧化还原平衡调节引起的肺纤维化。
