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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Humans
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-1beta / metabolism
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microglia / cytology
  • Microglia / immunology*
  • Microglia / metabolism
  • Monocytes / cytology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Signal Transduction

Substances

  • IL1B protein, human
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse