Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.
Acta Pharmacol Sin. 2023 Oct;44(10):2019-2036. doi: 10.1038/s41401-023-01105-7. Epub 2023 May 23.
Activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays important role in defending against infections, but its aberrant activation is causally linked to many inflammatory diseases, thus being a therapeutic target for these diseases. Theaflavin, one major ingredient of black tea, exhibits potent anti-inflammatory and anti-oxidative activities. In this study, we investigated the therapeutic effects of theaflavin against NLRP3 inflammasome activation in macrophages in vitro and in animal models of related diseases. We showed that theaflavin (50, 100, 200 μM) dose-dependently inhibited NLRP3 inflammasome activation in LPS-primed macrophages stimulated with ATP, nigericin or monosodium urate crystals (MSU), evidenced by reduced release of caspase-1p10 and mature interleukin-1β (IL-1β). Theaflavin treatment also inhibited pyroptosis as shown by decreased generation of N-terminal fragment of gasdermin D (GSDMD-NT) and propidium iodide incorporation. Consistent with these, theaflavin treatment suppressed ASC speck formation and oligomerization in macrophages stimulated with ATP or nigericin, suggesting reduced inflammasome assembly. We revealed that theaflavin-induced inhibition on NLRP3 inflammasome assembly and pyroptosis resulted from ameliorated mitochondrial dysfunction and reduced mitochondrial ROS production, thereby suppressing interaction between NLRP3 and NEK7 downstream of ROS. Moreover, we showed that oral administration of theaflavin significantly attenuated MSU-induced mouse peritonitis and improved the survival of mice with bacterial sepsis. Consistently, theaflavin administration significantly reduced serum levels of inflammatory cytokines including IL-1β and attenuated liver inflammation and renal injury of mice with sepsis, concomitant with reduced generation of caspase-1p10 and GSDMD-NT in the liver and kidney. Together, we demonstrate that theaflavin suppresses NLRP3 inflammasome activation and pyroptosis by protecting mitochondrial function, thus mitigating acute gouty peritonitis and bacterial sepsis in mice, highlighting a potential application in treating NLRP3 inflammasome-related diseases.
NLR 家族富含pyrin 域蛋白 3（NLRP3）炎性小体的激活在抵御感染中起着重要作用，但它的异常激活与许多炎症性疾病有关，因此成为这些疾病的治疗靶点。茶黄素是红茶的主要成分之一，具有很强的抗炎和抗氧化活性。在这项研究中，我们研究了茶黄素在体外和相关疾病动物模型中对巨噬细胞 NLRP3 炎性小体激活的治疗作用。我们表明，茶黄素（50、100、200μM）剂量依赖性地抑制 LPS 预处理的巨噬细胞中 NLRP3 炎性小体的激活，这些细胞受到 ATP、 Nigericin 或单钠尿酸盐晶体（MSU）的刺激，表现在 caspase-1p10 和成熟白细胞介素-1β（IL-1β）的释放减少。茶黄素治疗还抑制了焦亡，表现为 gasdermin D（GSDMD-NT）的 N 端片段和碘化丙啶掺入减少。与此一致，茶黄素处理抑制了巨噬细胞中 ATP 或 Nigericin 刺激下 ASC 斑点的形成和寡聚化，表明炎症小体的组装减少。我们揭示，茶黄素诱导的 NLRP3 炎性小体组装和焦亡的抑制是由于改善的线粒体功能障碍和减少的线粒体 ROS 产生，从而抑制了 ROS 下游 NLRP3 和 NEK7 之间的相互作用。此外，我们表明，口服茶黄素显著减轻了 MSU 诱导的小鼠腹膜炎，并提高了脓毒症小鼠的存活率。一致地，茶黄素给药显著降低了包括 IL-1β 在内的血清炎症细胞因子水平，并减轻了脓毒症小鼠的肝脏炎症和肾脏损伤，同时减少了肝脏和肾脏中 caspase-1p10 和 GSDMD-NT 的产生。总之，我们证明茶黄素通过保护线粒体功能抑制 NLRP3 炎性小体的激活和焦亡，从而减轻了小鼠急性痛风性腹膜炎和细菌性败血症，强调了其在治疗 NLRP3 炎性小体相关疾病中的潜在应用。
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