Department of Biomedical Science, School of Medicine, University of Missouri Kansas City, 2411 Holmes Street, Kansas City, MO 64108, U.S.A.
Department of Microbiology, School of Medicine, Nanchang University, NO 461 Bayi Road, Donghu District, Nanchang 330006, China.
Biochem J. 2020 Oct 30;477(20):3923-3934. doi: 10.1042/BCJ20200351.
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.
细胞焦亡是一种新发现的细胞程序性死亡形式，主要由胞内病原体感染触发，并对炎症反应有重要贡献。抑制细胞焦亡可能是炎症性疾病的一种潜在治疗靶点。然而，能够减少细胞焦亡的小分子仍然难以捉摸。在本研究中，我们从微生物天然产物文库中筛选了 155 种化学物质，发现 HSP90 抑制剂格尔德霉素（Geldanamycin）能显著挽救 LPS 和 Nigericin 诱导的 THP-1 细胞发生的细胞焦亡。同样，其他 HSP90 抑制剂，包括 Radicicol、17-DMAG 和 17-AAG，通过抑制细胞焦亡中的炎症小体/Caspase-1/GSDMD 信号通路，均能改善 THP-1 细胞的细胞焦亡。HSP90 抑制破坏了 NLRP3 的蛋白稳定性，NLRP3 是炎症小体的关键组成部分。此外，上调的 HSP70 也可能有助于这种作用。因此，HSP90 抑制可能是治疗细胞焦亡发挥作用的炎症性疾病的一种潜在治疗策略。
