Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review

• Published in: Inflammation Vol. 43; no. 1; pp. 17 - 23
• Main Authors: Wu, Danbin, Chen, Yefei, Sun, Yingxin, Gao, Qing, Li, Huhu, Yang, Zhengfei, Wang, Yangxue, Jiang, Xijuan, Yu, Bin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2020; Springer Nature B.V
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Caspase-1; Chloride; Chloride channels; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Immunology; Inflammasomes; Inflammasomes - drug effects; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Inflammation - metabolism; Internal Medicine; Intracellular; Literature reviews; Molecular Targeted Therapy; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Oligomerization; Pathology; Pharmacology/Toxicology; Potassium; Review; Rheumatology; Signal Transduction; Sulfones - pharmacology; ASC; NLRP3; potassium efflux; chloride efflux; MCC950; NEK7
• ISSN: 0360-3997; 1573-2576; 1573-2576
• DOI: 10.1007/s10753-019-01098-8

MCC950 has been proposed as a specific small molecule inhibitor that can selectively block NLRP3 inflammasome activation. However, the exact mechanism of its action is still ambiguous. Accumulating investigations imply that chloride efflux–dependent ASC speck oligomerization and potassium efflux–dependent activation of caspase-1 are the two relatively independent, but indispensable events for NLRP3 inflammasome activation. Previous studies suggested that influence of MCC950 on potassium efflux and its consequent events such as interaction between NEK7 and NLRP3 are limited. However, inhibiting chloride intracellular channel–dependent chloride efflux leads to a modification of inflammatory response, which is similar to the function of MCC950. Based on these findings, we shed new insights on the understanding of MCC950 that its function might correlate with chloride efflux, chloride intracellular channels, or other targets that act upstream of chloride efflux.