Lin Yuqing, Luo Tianyu, Weng Anli, Huang Xiaodi, Yao Yanqing, Fu Zhen, Li Yingwei, Liu Aijun, Li Xican, Chen Dongfeng, Pan Hao
Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Immunol. 2020 Dec 7;11:580593. doi: 10.3389/fimmu.2020.580593. eCollection 2020.
Gallic acid is an active phenolic acid widely distributed in plants, and there is compelling evidence to prove its anti-inflammatory effects. NLRP3 inflammasome dysregulation is closely linked to many inflammatory diseases. However, how gallic acid affects the NLRP3 inflammasome remains unclear. Therefore, in the present study, we investigated the mechanisms underlying the effects of gallic acid on the NLRP3 inflammasome and pyroptosis, as well as its effect on gouty arthritis in mice. The results showed that gallic acid inhibited lactate dehydrogenase (LDH) release and pyroptosis in lipopolysaccharide (LPS)-primed and ATP-, nigericin-, or monosodium urate (MSU) crystal-stimulated macrophages. Additionally, gallic acid blocked NLRP3 inflammasome activation and inhibited the subsequent activation of caspase-1 and secretion of IL-1β. Gallic acid exerted its inhibitory effect by blocking NLRP3-NEK7 interaction and ASC oligomerization, thereby limiting inflammasome assembly. Moreover, gallic acid promoted the expression of nuclear factor E2-related factor 2 (Nrf2) and reduced the production of mitochondrial ROS (mtROS). Importantly, the inhibitory effect of gallic acid could be reversed by treatment with the Nrf2 inhibitor ML385. NRF2 siRNA also abolished the inhibitory effect of gallic acid on IL-1β secretion. The results further showed that gallic acid could mitigate MSU-induced joint swelling and inhibit IL-1β and caspase 1 (p20) production in mice. Moreover, gallic acid could moderate MSU-induced macrophages and neutrophils migration into joint synovitis. In summary, we found that gallic acid suppresses ROS generation, thereby limiting NLRP3 inflammasome activation and pyroptosis dependent on Nrf2 signaling, suggesting that gallic acid possesses therapeutic potential for the treatment of gouty arthritis.
没食子酸是一种广泛分布于植物中的活性酚酸，有确凿证据证明其具有抗炎作用。NLRP3炎性小体失调与许多炎症性疾病密切相关。然而，没食子酸如何影响NLRP3炎性小体仍不清楚。因此，在本研究中，我们探究了没食子酸对NLRP3炎性小体和细胞焦亡的作用机制，以及其对小鼠痛风性关节炎的影响。结果表明，没食子酸可抑制脂多糖（LPS）预处理并用ATP、尼日利亚菌素或尿酸钠（MSU）晶体刺激的巨噬细胞中乳酸脱氢酶（LDH）的释放和细胞焦亡。此外，没食子酸可阻断NLRP3炎性小体的激活，并抑制随后的半胱天冬酶-1激活和IL-1β的分泌。没食子酸通过阻断NLRP3-NEK7相互作用和ASC寡聚化发挥其抑制作用，从而限制炎性小体的组装。此外，没食子酸可促进核因子E2相关因子2（Nrf2）的表达，并减少线粒体活性氧（mtROS）的产生。重要的是，没食子酸的抑制作用可通过用Nrf2抑制剂ML385处理来逆转。NRF2 siRNA也消除了没食子酸对IL-1β分泌的抑制作用。结果还表明，没食子酸可减轻MSU诱导的小鼠关节肿胀，并抑制IL-1β和半胱天冬酶1（p20）的产生。此外，没食子酸可减轻MSU诱导的巨噬细胞和中性粒细胞向关节滑膜炎的迁移。总之，我们发现没食子酸可抑制ROS生成，从而限制依赖于Nrf2信号的NLRP3炎性小体激活和细胞焦亡，这表明没食子酸具有治疗痛风性关节炎的潜力。
