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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zewinger, S; Reiser, J; Jankowski, V; Alansary, D; Hahm, E; Triem, S; Klug, M; Schunk, SJ; Schmit, D; Kramann, R; Körbel, C; Ampofo, E; Laschke, MW; Selejan, SR; Paschen, A; Herter, T; Schuster, S; Silbernagel, G; Sester, M; Sester, U; Aßmann, G; Bals, R; Kostner, G; Jahnen-Dechent, W; Menger, MD; Rohrer, L; März, W; Böhm, M; Jankowski, J; Kopf, M; Latz, E; Niemeyer, BA; Fliser, D; Laufs, U; Speer, T.
Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.
Nat Immunol. 2020; 21(1): 30-41.
Doi: 10.1038/s41590-019-0548-1
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PubMed
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- Co-Autor*innen der Med Uni Graz
- Kostner Gerhard
- März Winfried
- Silbernagel Günther
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- 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.