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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.

Original publication

DOI

10.1111/imm.13267

Type

Journal article

Journal

Immunology

Publication Date

01/2021

Volume

162

Pages

84 - 91

Addresses

Alzheimer's Research UK Oxford Drug Discovery Institute, University of Oxford, Oxford, UK.

Keywords

Animals, Mice, Inbred C57BL, Mice, Peritonitis, Inflammation, Protein Isoforms, Cytokines, Signal Transduction, Male, HSP90 Heat-Shock Proteins, Inflammasomes, NLR Family, Pyrin Domain-Containing 3 Protein