Skip to main content

Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.

Nature immunology

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

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.

PMID: 31819254

Participating cluster members