Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation

Stephen Zewinger, Jochen Reiser, Vera Jankowski, Dalia Alansary, Eunsil Hahm, Sarah Triem, Mira Klug, Stefan J. Schunk, David Schmit, Rafael Kramann, Christina Koerbel, Emmanuel Ampofo, Matthias W. Laschke, Simina-Ramona Selejan, Anna Paschen, Tobias Herter, Susanne Schuster, Guenther Silbernagel, Martina Sester, Urban SesterGunter Assmann, Robert Bals, Gerhard Kostner, Willi Jahnen-Dechent, Michael D. Menger, Lucia Rohrer, Winfried Maerz, Michael Boehm, Joachim Jankowski, Manfred Kopf, Eicke Latz, Barbara A. Niemeyer, Danilo Fliser, Ulrich Laufs, Thimoteus Speer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

89 Citations (Web of Science)

Abstract

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.

Original languageEnglish
Pages (from-to)30-41
Number of pages12
JournalNature Immunology
Volume21
Issue number1
DOIs
Publication statusPublished - Jan 2020

Keywords

  • OF-FUNCTION MUTATIONS
  • NLRP3 INFLAMMASOME
  • ENDOTHELIAL DYSFUNCTION
  • PATTERN-RECOGNITION
  • CELL-DEATH
  • APOC-III
  • PROTEIN
  • RECEPTOR
  • ADAPTER
  • CIII

Cite this