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MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice

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Perera, APP ORCID: 0000-0002-3674-9940, Fernando, R, Shinde, TS ORCID: 0000-0002-8551-5841, Gundamaraju, R, Southam, B, Sohal, SS ORCID: 0000-0001-9627-6498, Robertson, AAB, Schroder, K, Kunde, D ORCID: 0000-0002-6513-032X and Eri, R ORCID: 0000-0003-1688-8043 2018 , 'MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice' , Scientific Reports, vol. 8 , pp. 1-15 , doi: 10.1038/s41598-018-26775-w.

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Abstract

MCC950 a potent, highly specific small molecule inhibitor of canonical and noncanonical activation of NLRP3 inflammasome has been evaluated in a multitude of NLRP3 driven inflammatory diseases. However, the effect of MCC950 on colonic inflammation has not yet been reported. In the present study we investigated the effect of MCC950 in a spontaneous chronic colitis mouse model Winnie, which mimics human ulcerative colitis. Oral administration of 40 mg/kg MCC950 commencing at Winnie week seven for three weeks significantly improved body weight gain, colon length, colon weight to body weight ratio, disease activity index and histopathological scores. MCC950 significantly suppressed release of proinflammatory cytokines IL-1β, IL-18, IL1-α, IFNγ, TNF-α, IL6, IL17, chemokine MIP1a and Nitric Oxide in colonic explants. Moreover, MCC950 resulted in a significant decrease of IL-1β release and activation of caspase-1 in colonic explants and macrophage cells isolated from Winnie. Complete inhibition with MCC950 in Winnie colonic explants shows, for the first time, the contribution of inflammatory effects resulting exclusively from canonical and noncanonical NLRP3 inflammasome activation in colitis. Taken together, our results illustrate the efficacy of MCC950 in the treatment of murine ulcerative colitis and provides avenue for a potential novel therapeutic agent for human inflammatory bowel diseases.

Item Type: Article
Authors/Creators:Perera, APP and Fernando, R and Shinde, TS and Gundamaraju, R and Southam, B and Sohal, SS and Robertson, AAB and Schroder, K and Kunde, D and Eri, R
Keywords: colitis, IBD, NLRP3
Journal or Publication Title: Scientific Reports
Publisher: Nature Publishing Group
ISSN: 2045-2322
DOI / ID Number: 10.1038/s41598-018-26775-w
Copyright Information:

© The Author(s) 2018. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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