Carnosol inhibits inflammasome activation by directly targeting HSP90 to treat inflammasome-mediated diseases

Wei Shi,Hongbin Liu,Yongqiang Ai,Xiaohe Xiao,Xiaorong Hou,Tingting He,Yuming Guo,Ming Niu,Yan Liu,Guang Xu,Yuanyuan Chen,Nan Qin,Shubin Fu,Xiaoyan Zhan,Jiabo Wang,Zhilei Wang,Chunyu Wang,Yuan Gao,Zhaofang Bai

doi:10.1038/s41419-020-2460-x

Abstract

Aberrant activation of inflammasomes, a group of protein complexes, is pathogenic in a variety of metabolic and inflammation-related diseases. Here, we report that carnosol inhibits NLRP3 inflammasome activation by directly targeting heat-shock protein 90 (HSP90), which is essential for NLRP3 inflammasome activity, thereby treating inflammasome-mediated diseases. Our data demonstrate that carnosol inhibits NLRP3 inflammasome activation in primary mouse bone marrow-derived macrophages (BMDMs), THP-1 cells and human peripheral blood mononuclear cells (hPBMCs). Mechanistically, carnosol inhibits inflammasome activation by binding to HSP90 and then inhibiting its ATPase activity. In vivo, our results show that carnosol has remarkable therapeutic effects in mouse models of NLRP3 inflammasome-mediated diseases, including endotoxemia and nonalcoholic steatohepatitis (NASH). Our data also suggest that intraperitoneal administration of carnosol (120 mg/kg) once daily for two weeks is well tolerated in mice. Thus, our study reveals the inhibitory effect of carnosol on inflammasome activation and demonstrates that carnosol is a safe and effective candidate for the treatment of inflammasome-mediated diseases.

Highlights

Inflammasomes are multiprotein complexes that can be activated by pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) to trigger the catalytic activation of caspase-1, subsequently leading to pyroptosis and the production of interleukin 1β (IL-1β) and IL-181–3
Our results showed that carnosol inhibited caspase-1 and IL-1β production in a dosedependent manner, as well as the release of Lactate dehydrogenase (LDH) in LPSprimed bone marrow-derived macrophages (BMDMs) (Fig. 1a–d)
Our findings showed that carnosol inhibits inflammasomes by binding to heat-shock protein 90 (HSP90) and inhibiting its ATPase activity, which is essential for NLRP3 inflammasome activation

Summary

Introduction

Inflammasomes are multiprotein complexes that can be activated by pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) to trigger the catalytic activation of caspase-1, subsequently leading to pyroptosis and the production of interleukin 1β (IL-1β) and IL-181–3. Previous studies have confirmed that inflammasomes are involved in the initiation of various metabolic and inflammation-related diseases[4,5]. NLRP1, NLRP3, and NLRC4, as well as the cytosolic receptor AIM2, have been shown to form inflammasomes[12,13,14,15,16]. The NLRP3 inflammasome is the most well-characterized, it can be activated by many stimuli, including adenosine triphosphate (ATP), nigericin, monocrystalline sodium urate (MSU), SiO2, cholesterol crystals and amyloid-β aggregates[17,18,19]. The NLRP3 inflammasome contributes to the development of several human diseases, including gout, Alzheimer’s disease, enteritis and liver disease[4,8,20,21]. Several molecular compounds, including MCC950, OLT1177, Bay 11-7082, β-hydroxybutyrate glyburide, parthenolide, sulforaphane, glycyclamide, isoliquiritigenin

Methods

Results

Conclusion