Abstract
Pyroptosis is a recently discovered inflammatory form of programmed cell death which is mostly triggered by infection with intracellular pathogens and critically contributes to inflammation. Mitigating pyroptosis may be a potential therapeutic target in inflammatory diseases. However, small chemicals to reduce pyroptosis is still elusive. In the present study, we screened 155 chemicals from a microbial natural product library and found Geldanamycin, an HSP90 inhibitor, profoundly rescued THP-1 cells from pyroptosis induced by LPS plus Nigericin treatment. Consistently, other HSP90 inhibitors, including Radicicol, 17-DMAG and 17-AAG, all ameliorated pyroptosis in THP-1 cells by suppressing the inflammasome/Caspase-1/GSDMD signal pathway in pyroptosis. HSP90 inhibition compromised the protein stability of NLRP3, a critical component of the inflammasome. Moreover, up-regulated HSP70 may also contribute to this effect. HSP90 inhibition may thus be a potential therapeutic strategy in the treatment of inflammatory diseases in which pyroptosis plays a role.
Keywords:
NLRP3; THP-1; gasdemin D; inflammasome; pyroptosis.
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Benzoquinones / pharmacology*
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Caspase 1 / metabolism
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Cell Survival / drug effects
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HSP72 Heat-Shock Proteins / metabolism
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Inflammasomes / drug effects*
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Inflammasomes / metabolism
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Inflammation / drug therapy
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Inflammation / metabolism*
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Intracellular Signaling Peptides and Proteins / metabolism
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Lactams, Macrocyclic / pharmacology*
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Lipopolysaccharides / toxicity
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Macrolides / pharmacology
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NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
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Nigericin / toxicity
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Phosphate-Binding Proteins / metabolism
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Protein Stability
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Pyroptosis / drug effects*
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Signal Transduction / drug effects
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THP-1 Cells
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Up-Regulation
Substances
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Benzoquinones
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GSDMD protein, human
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HSP72 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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Inflammasomes
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Intracellular Signaling Peptides and Proteins
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Lactams, Macrocyclic
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Lipopolysaccharides
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Macrolides
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Phosphate-Binding Proteins
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17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
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tanespimycin
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Caspase 1
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Proteasome Endopeptidase Complex
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monorden
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Nigericin
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geldanamycin