Abstract
Uncontrolled activation of NLRP3 inflammasome initiates a series of human inflammatory diseases. Targeting NLRP3 inflammasome has attracted considerable attention in developing potential therapeutic interventions. Here, we reported that dehydrocostus lactone (DCL), a main component of Saussurea lappa from the traditional Chinese medicine, inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent interleukin (IL)-1β production in primary mouse macrophages and human peripheral blood mononuclear cells and exerted an inhibitory effect on NLRP3-driven inflammation. Mechanistically, DCL significantly blocked the ASC oligomerization, which is essential for the assembly of activated inflammasome. Importantly, in vivo experiments showed that DCL reduced IL-1β secretion and peritoneal neutrophils recruitment in LPS-mediated inflammation mouse model, which is demonstrated to be NLRP3 dependent. These results suggest that DCL is a potent pharmacological inhibitor of NLRP3 inflammasome and may be developed as a therapeutic drug for treating NLRP3-associated diseases.
Keywords:
ASC oligomerization; Dehydrocostus lactone; IL-1β; NLRP3.
Copyright © 2020 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / physiology
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CARD Signaling Adaptor Proteins / antagonists & inhibitors
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CARD Signaling Adaptor Proteins / metabolism
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Calcium-Binding Proteins / antagonists & inhibitors
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Calcium-Binding Proteins / physiology
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Caspase 1 / metabolism
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Chemotaxis, Leukocyte / drug effects*
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / physiology
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Drug Evaluation, Preclinical
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Drugs, Chinese Herbal / pharmacology*
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Female
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Humans
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Inflammasomes / drug effects*
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Inflammation / prevention & control*
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Interleukin-1beta / biosynthesis
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Lactones / pharmacology*
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Leukocytes, Mononuclear / drug effects*
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Lipopolysaccharides / toxicity
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Macrophages / drug effects*
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
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Neutrophils / drug effects
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Nigericin / pharmacology
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Poly I-C / pharmacology
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Polymerization / drug effects
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Sesquiterpenes / pharmacology*
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Specific Pathogen-Free Organisms
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Uric Acid / pharmacology
Substances
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Aim2 protein, mouse
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins
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DNA-Binding Proteins
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Drugs, Chinese Herbal
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Inflammasomes
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Interleukin-1beta
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Ipaf protein, mouse
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Lactones
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Lipopolysaccharides
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Pycard protein, mouse
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Sesquiterpenes
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Uric Acid
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dehydrocostus lactone
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Caspase 1
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Poly I-C
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Nigericin