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

Citation

Perera, AP and Fernando, R and Shinde, T and Gundamaraju, R and Southam, B and Sohal, SS and Robertson, AAB and Schroder, K and Kunde, D and Eri, R, MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice, Scientific Reports, 8 Article 8618. ISSN 2045-2322 (2018) [Refereed Article]


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Copyright Statement

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

DOI: doi:10.1038/s41598-018-26775-w

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 Details

Item Type:Refereed Article
Keywords:colitis, IBD, NLRP3
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Genetic Immunology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Digestive System Disorders
UTAS Author:Perera, AP (Mrs Agampodi Perera)
UTAS Author:Shinde, T (Ms Tanvi Shinde)
UTAS Author:Gundamaraju, R (Mr Rohit Gundamaraju)
UTAS Author:Southam, B (Mr Benjamin Southam)
UTAS Author:Sohal, SS (Dr Sukhwinder Sohal)
UTAS Author:Kunde, D (Dr Dale Kunde)
UTAS Author:Eri, R (Associate Professor Raj Eri)
ID Code:126519
Year Published:2018
Web of Science® Times Cited:26
Deposited By:Health Sciences
Deposited On:2018-06-15
Last Modified:2019-03-06
Downloads:147 View Download Statistics

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