Nod-like receptor family pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune receptor that senses organelle dysfunction induced by various stimuli, such as infectious, environmental, metabolic and drug stresses. Upon activation, NLRP3 forms an inflammasome with its adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1, to trigger the release of inflammatory cytokines. The development of effective anti-inflammatory drugs targeting the NLRP3 inflammasome is in high demand as its aberrant activation often causes inflammatory diseases. Here, we found that nanaomycin A (NNM-A), a quinone-based antibiotic isolated from Streptomyces, effectively inhibited NLRP3 inflammasome-mediated inflammatory responses induced by imidazoquinolines, including imiquimod. Interestingly, its epoxy derivative nanaomycin E (NNM-E) showed a comparable inhibitory effect against the NLRP3 inflammasome-induced release of interleukin (IL)-1β and IL-18 from macrophages, with a much lower toxicity than NNM-A. NNM-E inhibited ASC oligomerization and caspase-1 cleavage, both of which are hallmarks of NLRP3 inflammasome activation. NNM-E reduced mitochondrial damage and the production of reactive oxygen species, thereby preventing the activation of the NLRP3 inflammasome. NNM-E treatment markedly alleviated psoriasis-like skin inflammation induced by imiquimod. Collectively, NNM-E inhibits NLRP3 inflammasome activation by preventing mitochondrial dysfunction with little toxicity and showed an anti-inflammatory effect in vivo. Thus, NNM-E could be a potential lead compound for developing effective and safe anti-inflammatory agents for the treatment of NLRP3 inflammasome-mediated inflammatory diseases.

中文翻译：

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Nanaomycin E 通过防止线粒体功能障碍抑制 NLRP3 炎性体活化。

Nod 样受体家族含有 pyrin 结构域的 3 (NLRP3) 是一种胞质先天免疫受体，可感知各种刺激（如感染、环境、代谢和药物应激）诱导的细胞器功能障碍。激活后，NLRP3 与含有 caspase 募集结构域 (ASC) 和 caspase-1 的衔接蛋白凋亡相关斑点样蛋白形成炎性体，以触发炎性细胞因子的释放。开发针对 NLRP3 炎性体的有效抗炎药的需求量很大，因为其异常激活通常会导致炎性疾病。在这里，我们发现纳米霉素 A (NNM-A) 是一种从链霉菌中分离出来的基于醌的抗生素，可有效抑制由咪唑喹啉（包括咪喹莫特）诱导的 NLRP3 炎症小体介导的炎症反应。有趣的是，其环氧衍生物纳米霉素E（NNM-E）对NLRP3炎症小体诱导的巨噬细胞释放白细胞介素（IL）-1β和IL-18具有相当的抑制作用，其毒性远低于NNM-A。NNM-E 抑制 ASC 寡聚化和 caspase-1 裂解，这两者都是 NLRP3 炎性体激活的标志。NNM-E 减少了线粒体损伤和活性氧的产生，从而阻止了 NLRP3 炎性体的激活。NNM-E 治疗显着减轻了咪喹莫特诱导的银屑病样皮肤炎症。总的来说，NNM-E 通过阻止线粒体功能障碍来抑制 NLRP3 炎症小体的活化，毒性很小，并在体内显示出抗炎作用。因此，