期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2022.822236
关键词
NLRP3 inflammasome; manoalide; inhibitor; inflammatory diseases; EAE
资金
- National Key research and development program of China [2018YFA0507403, 2019YFA0508503]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB29030102]
- National Natural Science Foundation of China [82003765, 81821001, 31770991, 82130107]
- Fundamental Research Funds for the Central Universities
- University Synergy Innovation Program of Anhui Province [GXXT-2019-026]
- Natural Science Foundation of Anhui Province [1908085QC99]
Activation of NLRP3 inflammasome leads to cell pyroptosis and inflammatory cytokine secretion, and is involved in the development of various diseases. Manoalide, identified as a selective small molecule inhibitor of NLRP3, can inhibit NLRP3 activation through multiple mechanisms and alleviate the pathogenesis of related diseases.
The activation of NLRP3 inflammasome leads to cell pyroptosis and inflammatory cytokines secretion and gets involved in the development of many diseases, such as neuroinflammation and metabolic syndrome, but the drugs targeting NLRP3 are not clinically available for now. Through screening the small molecule library, we found that manoalide is a highly selective small molecule inhibitor of NLRP3. Mechanismly, manoalide inhibited the NLRP3 inflammasome activation by acting downstream of potassium efflux, chloride efflux and mitochondrial dysfunction. Moreover, manoalide blocked the interaction between NEK7 and NLRP3 by covalently binding to Lys 377 of the NLRP3 protein. Treatment of manoalide relieved the pathogenesis of experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our results identify manoalide as a selective and covalent NLRP3 inhibitor and suggest it has the potential for the treatment of NLRP3-associated diseases.
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