1. 1'-Acetoxychavicol acetate inhibits NLRP3-dependent inflammasome activation via mitochondrial ROS suppression.
- Author
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Sok SPM, Ori D, Wada A, Okude H, Kawasaki T, Momota M, Nagoor NH, and Kawai T
- Subjects
- Animals, Caspase 1 metabolism, Cells, Cultured, Disease Models, Animal, Humans, Inflammation metabolism, Interleukin-1beta metabolism, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Monocytes drug effects, Monocytes metabolism, Peritonitis drug therapy, Peritonitis metabolism, Phagocytosis drug effects, Pyroptosis drug effects, THP-1 Cells drug effects, THP-1 Cells metabolism, Benzyl Alcohols pharmacology, Inflammasomes drug effects, Inflammasomes metabolism, Mitochondria drug effects, Mitochondria metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Reactive Oxygen Species metabolism
- Abstract
The nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing (NLRP) 3 inflammasome is a multiprotein complex that triggers Caspase-1-mediated IL-1β production and pyroptosis, and its dysregulation is associated with the pathogenesis of inflammatory diseases. 1'-Acetoxychavicol acetate (ACA) is a natural compound in the rhizome of tropical ginger Alpinia species with anti-microbial, anti-allergic and anti-cancer properties. In this study, we found that ACA suppressed NLRP3 inflammasome activation in mouse bone marrow-derived macrophages and human THP-1 monocytes. ACA inhibited Caspase-1 activation and IL-1β production by NLRP3 agonists such as nigericin, monosodium urate (MSU) crystals, and ATP. Moreover, it suppressed oligomerization of the adapter molecule, apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1-mediated cleavage of pyroptosis executor Gasdermin D. Mechanistically, ACA inhibited generation of mitochondrial reactive oxygen species (ROS) and prevented release of oxidized mitochondrial DNA, which trigger NLRP3 inflammasome activation. ACA also prevented NLRP3 inflammasome activation in vivo, as evidenced in the MSU crystal-induced peritonitis and dextran sodium sulfate-induced colitis mouse models accompanied by decreased Caspase-1 activation. Thus, ACA is a potent inhibitor of the NLRP3 inflammasome for prevention of NLRP3-associated inflammatory diseases., (© The Japanese Society for Immunology. 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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