Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity

PLoS One. 2020 Aug 18;15(8):e0237030. doi: 10.1371/journal.pone.0237030. eCollection 2020.

Abstract

Curative therapeutic options for a number of immunological disorders remain to be established, and approaches for identifying drug candidates are relatively limited. Furthermore, phenotypic screening methods using induced pluripotent stem cell (iPSC)-derived immune cells or hematopoietic cells need improvement. In the present study, using immortalized monocytic cell lines derived from iPSCs, we developed a high-throughput screening (HTS) system to detect compounds that inhibit IL-1β secretion and NLRP3 inflammasome activation from activated macrophages. The iPSCs were generated from a patient with neonatal onset multisystem inflammatory disease (NOMID) as a model of a constitutively activated NLRP3 inflammasome. HTS of 4,825 compounds including FDA-approved drugs and compounds with known bioactivity identified 7 compounds as predominantly IL-1β inhibitors. Since these compounds are known inflammasome inhibitors or derivatives of, these results prove the validity of our HTS system, which can be a versatile platform for identifying drug candidates for immunological disorders associated with monocytic lineage cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism
  • Caspase 1 / metabolism
  • Cell Line
  • Cells, Cultured
  • Cryopyrin-Associated Periodic Syndromes / immunology
  • Cryopyrin-Associated Periodic Syndromes / physiopathology
  • High-Throughput Screening Assays / methods*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Inflammasomes / metabolism*
  • Inflammasomes / physiology
  • Inflammation / metabolism
  • Interleukin-1beta
  • Macrophages / metabolism
  • Monocytes / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / physiology

Substances

  • Carrier Proteins
  • IL1B protein, human
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Caspase 1

Grants and funding

This work was supported by the grant for the Core Center for iPS Cell Research of Research Center Network for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) [T.N. and M.K.S.]; the Program for Intractable Diseases Research utilizing Disease-specific iPS cells of AMED (15652070 and 17935423) [T.N. and M.K.S.]; Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) of AMED (14525046) [M.K.S.]; Practical Research Project for Rare/Intractable Diseases of AMED (17930095) [M.K.S.] and the Japan Society for the Promotion of Science (JSPS) KAKENHI grant number 13389802 [M.K.S.]. Nippon Shinyaku, CO., LTD., provided support in the form of salaries to the authors [R.S. and H.N.]. The specific roles of R.S. and H.N. are articulated in the ‘Author Contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.