Heat shock protein 90 inhibitors suppress pyroptosis in THP-1 cells

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.