A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

Rebecca C Coll^1,2, Avril A B Robertson², Jae Jin Chae³, Sarah C Higgins¹, Raúl Muñoz-Planillo⁴, Marco C Inserra^2,5, Irina Vetter^2,5, Lara S Dungan¹, Brian G Monks⁶, Andrea Stutz⁶, Daniel E Croker², Mark S Butler², Moritz Haneklaus¹, Caroline E Sutton¹, Gabriel Núñez⁴, Eicke Latz^6–8, Daniel L Kastner³, Kingston H G Mills¹, Seth L Masters⁹, Kate Schroder², Matthew A Cooper² & Luke A J O’Neill¹

Nat Med. 2015 Mar; 21(3):248-55. doi: 10.1038/nm.3806. Epub 2015 Feb 16.

Speaker: Yeh, Zheng-Wei (葉正偉)                                        Time: 13:00~14:00, Nov. 18, 2015

Commentator: Tsai, Yau-Sheng (蔡曜聲)副教授           Place: Room 601

Abstract:

Inflammasome NLRP3 is one of the NLR family protein that response to pathogens infection and stress, then it leads to inflammatory responses by signal transduction then IL-1β and IL-18 production, IL-1β and IL-18 mediates the cell death pathway called pyroptosis. Deregulation of NLRP3 can causes varieties of inflammatory diseases like cryopyrin-associated periodic syndrome (CAPS) or complex diseases like multiple sclerosis, type 2 diabetes, Alzheimer's diseases and atherosclerosis. Former treatments for NLRP3-related diseases mainly target IL-1 secretion; recently some small molecules had found that they can inhibit NLRP3 activation, like glyburide. Because MCC950 has similar structures with glyburide, in this study, authors tested effects of a small molecule compound: MCC950 on NLRP3. Author tested MCC950 with varieties tests associated with NLRP3 activation or other inflammasome. Results showed that MCC950 can significant decrease IL-1β secretion in NLRP3 activation ex vivo and in vivo, MCC950 can also attenuate NLRP3-induced oligomerization, EAE severity and MCC950 has effects on CAPS or MWS. However, MCC950 has little inhibition on PRRs other than NLRP3, NLRP3-ASC or NLRP3-NLRP3 interaction, TLR signaling and NLRP3 priming. In conclusion, authors found that MCC950 can effectively inhibit NLRP3 induced IL-1β secretion. Authors would further explore mechanisms how MCC950 effects on NLRP3, authors assumed that MCC950 may target NLRP3 itself or NLRP3 activation. Future developments of MCC950 may results in a new therapies for inflammatory diseases.

Reference:

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