Development of a characterised tool kit for the interrogation of NLRP3 inflammasomedependent responses

Elena Redondo Castro; Dorte Faust; Simon Fox; Alex Baldwin; Simon Osborne; Michael Haley; E Karran; Hugh Nuthall; Peter J Atkinson; Lee A Dawson; Carol Routledge; Stuart Allan; Sally Freeman; Janet Brownlees; David Brough

doi:10.1038/s41598-018-24029-3

Development of a characterised tool kit for the interrogation of NLRP3 inflammasomedependent responses

Elena Redondo Castro, Dorte Faust, Simon Fox, Alex Baldwin, Simon Osborne, Michael Haley, E Karran, Hugh Nuthall, Peter J Atkinson, Lee A Dawson, Carol Routledge, Stuart Allan, Sally Freeman, Janet Brownlees, David Brough

Research output: Contribution to journal › Article › peer-review

Abstract

Inflammation is an established contributor to disease and the NLRP3 inflammasome is emerging as a potential therapeutic target. A number of small molecule inhibitors of the NLRP3 pathway have been described. Here we analysed the most promising of these inhibitor classes side by side to assess relative potency and selectivity for their respective putative targets.
Assessed using ASC inflammasome-speck formation, and release of IL-1β, in both human monocyte/macrophage THP1 cells and in primary mouse microglia, we compared the relative potency and selectivity of P2X7 inhibitors, inflammasome inhibitors (diarylsulfonylurea vs. the NBC series), and caspase-1 inhibitors. In doing so we are now able to provide a well characterised small molecule tool kit for interrogating and validating inflammasome-dependent
responses with a range of nanomolar potency inhibitors against established points in the inflammasome pathway.

Original language	English
Journal	Scientific Reports
Early online date	4 Apr 2018
DOIs	https://doi.org/10.1038/s41598-018-24029-3
Publication status	Published - 2018

Keywords

P2X7 receptor
Nlrp3 inflammasome
Interleukin-1
caspase-1
inflammation

Research Beacons, Institutes and Platforms

Manchester Institute for Collaborative Research on Ageing

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10.1038/s41598-018-24029-3Licence: CC BY

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Redondo Castro, E., Faust, D., Fox, S., Baldwin, A., Osborne, S., Haley, M., Karran, E., Nuthall, H., Atkinson, P. J., Dawson, L. A., Routledge, C., Allan, S., Freeman, S., Brownlees, J., & Brough, D. (2018). Development of a characterised tool kit for the interrogation of NLRP3 inflammasomedependent responses. Scientific Reports. https://doi.org/10.1038/s41598-018-24029-3

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abstract = "Inflammation is an established contributor to disease and the NLRP3 inflammasome is emerging as a potential therapeutic target. A number of small molecule inhibitors of the NLRP3 pathway have been described. Here we analysed the most promising of these inhibitor classes side by side to assess relative potency and selectivity for their respective putative targets.Assessed using ASC inflammasome-speck formation, and release of IL-1β, in both human monocyte/macrophage THP1 cells and in primary mouse microglia, we compared the relative potency and selectivity of P2X7 inhibitors, inflammasome inhibitors (diarylsulfonylurea vs. the NBC series), and caspase-1 inhibitors. In doing so we are now able to provide a well characterised small molecule tool kit for interrogating and validating inflammasome-dependentresponses with a range of nanomolar potency inhibitors against established points in the inflammasome pathway.",

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author = "{Redondo Castro}, Elena and Dorte Faust and Simon Fox and Alex Baldwin and Simon Osborne and Michael Haley and E Karran and Hugh Nuthall and Atkinson, {Peter J} and Dawson, {Lee A} and Carol Routledge and Stuart Allan and Sally Freeman and Janet Brownlees and David Brough",

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AU - Redondo Castro, Elena

AU - Faust, Dorte

AU - Fox, Simon

AU - Baldwin, Alex

AU - Osborne, Simon

AU - Haley, Michael

AU - Karran, E

AU - Nuthall, Hugh

AU - Atkinson, Peter J

AU - Dawson, Lee A

AU - Routledge, Carol

AU - Allan, Stuart

AU - Freeman, Sally

AU - Brownlees, Janet

AU - Brough, David

PY - 2018

Y1 - 2018

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AB - Inflammation is an established contributor to disease and the NLRP3 inflammasome is emerging as a potential therapeutic target. A number of small molecule inhibitors of the NLRP3 pathway have been described. Here we analysed the most promising of these inhibitor classes side by side to assess relative potency and selectivity for their respective putative targets.Assessed using ASC inflammasome-speck formation, and release of IL-1β, in both human monocyte/macrophage THP1 cells and in primary mouse microglia, we compared the relative potency and selectivity of P2X7 inhibitors, inflammasome inhibitors (diarylsulfonylurea vs. the NBC series), and caspase-1 inhibitors. In doing so we are now able to provide a well characterised small molecule tool kit for interrogating and validating inflammasome-dependentresponses with a range of nanomolar potency inhibitors against established points in the inflammasome pathway.

KW - P2X7 receptor

KW - Nlrp3 inflammasome

KW - Interleukin-1

KW - caspase-1

KW - inflammation

U2 - 10.1038/s41598-018-24029-3

DO - 10.1038/s41598-018-24029-3

M3 - Article

SN - 2045-2322

JO - Scientific Reports

JF - Scientific Reports

ER -

Development of a characterised tool kit for the interrogation of NLRP3 inflammasomedependent responses

Abstract

Keywords

Research Beacons, Institutes and Platforms

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