Nanaomycin E inhibits NLRP3 inflammasome activation by preventing mitochondrial dysfunction

Author:

Matsui Yudai1,Takemura Naoki2,Shirasaki Yoshitaka3,Takahama Michihiro45,Noguchi Yoshihiko67,Ikoma Kenta2,Pan Yixi2,Nishida Shuhei2,Taura Manabu2,Nakayama Akiyoshi48ORCID,Funatsu Takashi3,Misawa Takuma9,Harada Yoshie1011,Sunazuka Toshiaki67,Saitoh Tatsuya2412

Affiliation:

1. Laboratory of Bioresponse Regulation, School of Pharmaceutical Sciences, Osaka University , Osaka , Japan

2. Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University , Osaka , Japan

3. Laboratory of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , Tokyo , Japan

4. Division of Inflammation Biology, Institute of Advanced Medical Sciences, Tokushima University , Tokushima , Japan

5. Pritzker School of Molecular Engineering, The University of Chicago , Chicago, IL , USA

6. Laboratory of Bioorganic Chemistry, Kitasato Institute for Life Sciences & Graduate School of Infection Control Sciences, Kitasato University , Tokyo , Japan

7. Ōmura Satoshi Memorial Institute, Kitasato University , Tokyo , Japan

8. Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College , Saitama , Japan

9. Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences , Kanagawa , Japan

10. Laboratory for Nanobiology, Institute for Protein Research, Osaka University , Osaka , Japan

11. Center for Quantum Information and Quantum Biology, Institute for Open and Transdisciplinary Research Initiatives, Osaka University , Osaka , Japan

12. Global Center for Medical Engineering and Informatics, Osaka University , Osaka , Japan

Abstract

Abstract 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.

Funder

Japan Society for the Promotion of Science

Ministry of Education, Culture, Sports, Science and Technology

Kobayashi Foundation

Kato Memorial Bioscience Foundation

Platform Project for Supporting Drug Discovery and Life Science Research

Basis for Supporting Innovative Drug Discovery and Life Science Research

BINDS

Publisher

Oxford University Press (OUP)

Subject

Immunology,General Medicine,Immunology and Allergy

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