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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
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The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation

Masahiro Okada1, Atsushi Matsuzawa2, Akihiko Yoshimura3

  • 1From the Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, the Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, and.

The Journal of Biological Chemistry
|October 8, 2014
PubMed

Insights

Lysosome rupture activates the TAK1-JNK pathway, crucial for NLRP3 inflammasome activation. This pathway, regulated by calcium ions and calcium/calmodulin-dependent protein kinase type II, is key to inflammasome signaling.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • Lysosome rupture is a known trigger for NLRP3 inflammasome activation in macrophages.
  • The precise molecular mechanisms linking lysosome damage to inflammasome activation remain incompletely elucidated.

Purpose of the Study:

  • To investigate the role of the TAK1-JNK pathway in lysosome rupture-induced NLRP3 inflammasome activation.
  • To identify upstream regulators of the TAK1-JNK pathway in this context.

Main Methods:

  • Utilized cell-based assays to monitor inflammasome activation and pathway signaling.
  • Investigated the involvement of calcium ions and specific kinases in the signaling cascade.

Main Results:

  • Demonstrated that lysosome rupture activates the TAK1-JNK pathway (a MAPK signaling pathway).
  • Showed TAK1-JNK pathway activation is essential for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization and complete NLRP3 inflammasome activation.
  • Identified sustained TAK1-JNK pathway activation by Ca(2+) ions and upstream regulation by calcium/calmodulin-dependent protein kinase type II.

Conclusions:

  • The TAK1-JNK pathway is a critical mediator of lysosome rupture-induced NLRP3 inflammasome activation.
  • Calcium signaling and calcium/calmodulin-dependent protein kinase type II play specific regulatory roles in this process.
Keywords:
Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)InflammasomeInnate ImmunityLysosome RuptureMitogen-activated Protein Kinase (MAPK)NLRP3Signal TransductionTAK1c-Jun N-terminal Kinase (JNK)siRNA Screen

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