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.