2. Academic Validation
  3. Development of a characterised tool kit for the interrogation of NLRP3 inflammasome-dependent responses

Development of a characterised tool kit for the interrogation of NLRP3 inflammasome-dependent responses

  • Sci Rep. 2018 Apr 4;8(1):5667. doi: 10.1038/s41598-018-24029-3.
Elena Redondo-Castro 1,  Dorte Faust 2,  Simon Fox 2,  Alex G Baldwin 3,  Simon Osborne 2,  Michael J Haley 1,  Eric Karran 4,  Hugh Nuthall 5,  Peter J Atkinson 6,  Lee A Dawson 7,  Carol Routledge 8,  Stuart M Allan 1,  Sally Freeman 3,  Janet Brownlees 2,  David Brough 9
Affiliations

Affiliations

  • 1 Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
  • 2 LifeArc, Accelerator Building, SBC Campus, Stevenage, SG1 2FX, UK.
  • 3 Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
  • 4 Abbvie, Foundational Neuroscience Centre, Cambridge, Massachusetts, USA.
  • 5 Eli Lilly Research Centre, Windlesham, Surrey, GU20 6PH, UK.
  • 6 Eisai Limited, European Knowledge Centre, Hatfield, Herts, AL10 9SN, UK.
  • 7 Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge, CB4 0QA, UK.
  • 8 Alzheimer's Research UK, 3 Riverside, Granta Park, Cambridge, CB21 6AD, UK.
  • 9 Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK. david.brough@manchester.ac.uk.
PMID: 29618797 DOI: 10.1038/s41598-018-24029-3
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.

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