Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation

• Published in: Nature immunology Vol. 21; no. 1; pp. 30 - 41
• Main Authors: Zewinger, Stephen, Reiser, Jochen, Jankowski, Vera, Alansary, Dalia, Hahm, Eunsil, Triem, Sarah, Klug, Mira, Schunk, Stefan J., Schmit, David, Kramann, Rafael, Körbel, Christina, Ampofo, Emmanuel, Laschke, Matthias W., Selejan, Simina-Ramona, Paschen, Anna, Herter, Tobias, Schuster, Susanne, Silbernagel, Günther, Sester, Martina, Sester, Urban, Aßmann, Gunter, Bals, Robert, Kostner, Gerhard, Jahnen-Dechent, Willi, Menger, Michael D., Rohrer, Lucia, März, Winfried, Böhm, Michael, Jankowski, Joachim, Kopf, Manfred, Latz, Eicke, Niemeyer, Barbara A., Fliser, Danilo, Laufs, Ulrich, Speer, Thimoteus
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2020; Nature Publishing Group
• Subjects: 631/250/2504/342; 631/250/256/2177; 631/250/262/2106/2517; Acute Kidney Injury - immunology; Acute Kidney Injury - pathology; Adapter proteins; Adaptor Proteins, Signal Transducing; Analysis; Animal models; Animals; Apolipoprotein C-III - genetics; Apolipoprotein C-III - immunology; Apolipoproteins; Arteriosclerosis; Atherosclerosis; Biomedical and Life Sciences; Biomedicine; Blood lipids; Caspase 8 - metabolism; Caspase-8; Cell activation; Cell Line; Computer software industry; Development and progression; Dimerization; Disease Models, Animal; HEK293 Cells; Humans; Immunology; Infectious Diseases; Inflammasomes; Inflammasomes - immunology; Inflammation; Inflammation - genetics; Inflammation - immunology; Kidney diseases; Kidney Diseases - immunology; Kidney Diseases - pathology; Kidneys; Lipoproteins; Lyn protein; Medical colleges; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Monocytes; Monocytes - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Scientific equipment and supplies industry; Syk protein; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - metabolism; Toll-like receptors; United States; Germany
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-019-0548-1

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. Overabundance of apolipoprotein C3 (ApoC3) is associated with atherosclerosis. Speer and colleagues demonstrate that ApoC3 activates the NLRP3 inflammasome via a non-canonical pathway contributing to inflammation and development of atherosclerosis.