期刊
PHYTOMEDICINE
卷 80, 期 -, 页码 -出版社
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2020.153398
关键词
Celastrol; NLRP3 inflammasome; IL-1 beta; Liver injury; Gouty arthritis; Deubiquitination
资金
- Natural Science Foundation of China [U1801284, 81573675, 81622050, 81873209, 81673709, 81973718, 81903821]
- National Key Research and Development Program of China [2017YFC1700404]
- Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [2017BT01Y036]
- GDUPS
- Guangdong Science and Technology Foundation [2017A030306004, 2019A1515010909]
- Program of Hong Kong Scholar [XJ2016017]
- Science and Technology Program of Guangzhou [201903010062, 907158833068]
- Youth Top-notch Talent Support Program of Guangdong Province [2016TQ03R586]
- K. C. Wong Education Foundation
Celastrol suppresses NLRP3 inflammasome activation in P. acnes/LPS-induced liver damage and MSU-induced gouty arthritis through inhibiting K63 deubiquitination of NLRP3, providing a novel insight into the inhibition of celastrol on NLRP3 inflammasome and supporting its potential application in the treatment of inflammation-related diseases.
Background: Celastrol, a pentacyclic triterpenoid quinonemethide isolated from several spp. of Celastraceae family, exhibits anti-inflammatory activities in a variety of diseases including arthritis. Purpose: This study aims to investigate whether the inhibition of NLRP3 inflammasome is engaged in the antiinflammatory activities of celastrol and delineate the underlying mechanism. Methods: The influence of celastrol on NLRP3 inflammasome activation was firstly studied in lipopolysaccharide (LPS)-primed mouse bone marrow-derived macrophages (BMDMs) and phorbol 12-myristate 13-acetate (PMA)-primed THP-1 cells treated with nigericin. Reconstituted inflammasome was also established by co-transfecting NLRP3, ASC, pro-caspase-1 and pro-IL-1 beta in HEK293T cells. The changes of inflammasome components including NLRP3, ASC, pro-caspase-1/caspase-1 and pro-IL-1 beta/IL-1 beta were examined by enzyme-linked immunosorbent assay (ELISA), western blotting and immunofluorescence. Furthermore, Propionibacterium acnes (P. acnes)/LPS-induced liver injury and monosodium urate (MSU)-induced gouty arthritis in mice were employed in vivo to validate the inhibitory effect of celastrol on NLRP3 inflammasome. Results: Celastrol significantly suppressed the cleavage of pro-caspase-1 and pro-IL-1p, while not affecting the protein expressions of NLRP3, ASC, pro-caspase-1 and pro-IL-1p in THP-1 cells, BMDMs and HEK293T cells. Celastrol suppressed NLRP3 inflammasome activation and alleviated P. acnes/LPS-induced liver damage and MSU-induced gouty arthritis. Mechanism study revealed that celastrol could interdict K63 deubiquitination of NLRP3, which may concern interaction of celastrol and BRCA1/BRCA2-containing complex subunit 3 (BRCC3), and thereby prohibited the formation of NLRP3, ASC and pro-caspase-1 complex to block the generation of mature IL-1 beta. Conclusion: Celastrol suppresses NLRP3 inflammasome activation in P. acnes/LPS-induced liver damage and MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3, which presents a novel insight into inhibition of celastml on NLRP3 inflammasome and provides more evidences for its application in the therapy of inflammation-related diseases.
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