Nanaomycin E inhibits NLRP3 inflammasome activation by preventing mitochondrial dysfunction
Nanaomycin E inhibits NLRP3 inflammasome activation by preventing mitochondrial dysfunction
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Nanaomycin E 通过防止线粒体功能障碍抑制 NLRP3 炎性体激活
DOI：
10.1093/intimm/dxac028
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发表时间：
2022
影响因子：
4.4
通讯作者：
Saitoh Tatsuya
中科院分区：
文献类型：
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作者：
Matsui Yudai;Takemura Naoki;Shirasaki Yoshitaka;Takahama Michihiro;Noguchi Yoshihiko;Ikoma Kenta;Pan Yixi;Nishida Shuhei;Taura Manabu;Nakayama Akiyoshi;Funatsu Takashi;Misawa Takuma;Harada Yoshie;Sunazuka Toshiaki;Saitoh Tatsuya
nod样受体家族pyrin domain-containing 3 （NLRP3）是一种细胞质先天免疫受体，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与其接头蛋白凋亡相关斑点样蛋白形成炎性小体，其中含有caspase募集结构域（ASC）和caspase-1，从而触发炎性细胞因子的释放。由于NLRP3炎性小体的异常激活常引起炎症性疾病，因此开发有效的抗炎药物是迫切需要的。本研究发现，纳米霉素A （NNM-A）是一种从链霉菌中分离出来的醌类抗生素，可有效抑制咪唑喹啉类药物（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减少线粒体损伤和活性氧的产生，从而阻止NLRP3炎性体的激活。NNM-E治疗可明显减轻咪喹莫特引起的牛皮癣样皮肤炎症。总的来说，NNM-E通过防止线粒体功能障碍来抑制NLRP3炎性体的激活，毒性很小，并且在体内显示出抗炎作用。因此，NNM-E可能是开发有效且安全的抗炎药的潜在先导化合物，用于治疗NLRP3炎症小体介导的炎症性疾病。
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 fromStreptomyces, 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 effectin 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.