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

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 i...

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Autores principales: Perera, Agampodi Promoda, Fernando, Ruchira, Shinde, Tanvi, Gundamaraju, Rohit, Southam, Benjamin, Sohal, Sukhwinder Singh, Robertson, Avril A. B., Schroder, Kate, Kunde, Dale, Eri, Rajaraman
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988655/
https://www.ncbi.nlm.nih.gov/pubmed/29872077
http://dx.doi.org/10.1038/s41598-018-26775-w
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author Perera, Agampodi Promoda
Fernando, Ruchira
Shinde, Tanvi
Gundamaraju, Rohit
Southam, Benjamin
Sohal, Sukhwinder Singh
Robertson, Avril A. B.
Schroder, Kate
Kunde, Dale
Eri, Rajaraman
author_facet Perera, Agampodi Promoda
Fernando, Ruchira
Shinde, Tanvi
Gundamaraju, Rohit
Southam, Benjamin
Sohal, Sukhwinder Singh
Robertson, Avril A. B.
Schroder, Kate
Kunde, Dale
Eri, Rajaraman
author_sort Perera, Agampodi Promoda
collection PubMed
description 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.
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spelling pubmed-59886552018-06-20 MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice Perera, Agampodi Promoda Fernando, Ruchira Shinde, Tanvi Gundamaraju, Rohit Southam, Benjamin Sohal, Sukhwinder Singh Robertson, Avril A. B. Schroder, Kate Kunde, Dale Eri, Rajaraman Sci Rep Article 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. Nature Publishing Group UK 2018-06-05 /pmc/articles/PMC5988655/ /pubmed/29872077 http://dx.doi.org/10.1038/s41598-018-26775-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Perera, Agampodi Promoda
Fernando, Ruchira
Shinde, Tanvi
Gundamaraju, Rohit
Southam, Benjamin
Sohal, Sukhwinder Singh
Robertson, Avril A. B.
Schroder, Kate
Kunde, Dale
Eri, Rajaraman
MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
title MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
title_full MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
title_fullStr MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
title_full_unstemmed MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
title_short MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
title_sort mcc950, a specific small molecule inhibitor of nlrp3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988655/
https://www.ncbi.nlm.nih.gov/pubmed/29872077
http://dx.doi.org/10.1038/s41598-018-26775-w
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