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Inhibition of the NLRP3 inflammasome by HSP90 inhibitors
Author(s) -
Nizami Sohaib,
Arunasalam Kanisa,
Green Jack,
Cook James,
Lawrence Catherine B.,
ZarganesTzitzikas Tryfon,
Davis John B.,
Di Daniel Elena,
Brough David
Publication year - 2021
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.13267
Subject(s) - inflammasome , inflammation , in vivo , hsp90 , hsp90 inhibitor , secretion , pharmacology , cytokine , biology , immunology , heat shock protein , biochemistry , microbiology and biotechnology , gene
Summary Excessive and dysregulated inflammation is known to contribute to disease progression. HSP90 is an intracellular chaperone known to regulate inflammatory processes including the NLRP3 inflammasome and secretion of the pro‐inflammatory cytokine interleukin(IL)‐1β. Here, primarily using an in vitro inflammasome ASC speck assay, and an in vivo model of murine peritonitis, we tested the utility of HSP90 inhibitors as anti‐inflammatory molecules. We report that the HSP90 inhibitor EC144 effectively inhibited inflammatory processes including priming and activation of NLRP3 in vitro and in vivo . A specific inhibitor of the β HSP90 isoform was ineffective suggesting the importance of the α isoform in inflammatory signalling. EC144 inhibited IL‐1β and IL‐6 in vivo when administered orally, and was brain‐penetrant. These data suggest that HSP90 inhibitors may be useful for targeting inflammation in diverse diseases that are worsened by the presence of inflammation.