Journal Article

DZNE-2020-00372

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.

Zewinger, S. ; Reiser, J. ; Jankowski, V. ; Alansary, D. ; Hahm, E. ; Triem, S. ; Klug, M. ; Schunk, S. J. ; Schmit, D. ; Kramann, R. ; Körbel, C. ; Ampofo, E. ; Laschke, M. W. ; Selejan, S.-R. ; Paschen, A. ; Herter, T. ; Schuster, S. ; Silbernagel, G. ; Sester, M. ; Sester, U. ; Aßmann, G. ; Bals, R. ; Kostner, G. ; Jahnen-Dechent, W. ; Menger, M. D. ; Rohrer, L. ; März, W. ; Böhm, M. ; Jankowski, J. ; Kopf, M. ; Latz, E.DZNE* ; Niemeyer, B. A. ; Fliser, D. ; Laufs, U. ; Speer, T. (Corresponding author)

2020
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/s41590-019-0548-1

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.

Keyword(s): Acute Kidney Injury: immunology (MeSH) ; Acute Kidney Injury: pathology (MeSH) ; Adaptor Proteins, Signal Transducing (MeSH) ; Animals (MeSH) ; Apolipoprotein C-III: genetics (MeSH) ; Apolipoprotein C-III: immunology (MeSH) ; Caspase 8: metabolism (MeSH) ; Cell Line (MeSH) ; Disease Models, Animal (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Inflammasomes: immunology (MeSH) ; Inflammation: genetics (MeSH) ; Inflammation: immunology (MeSH) ; Kidney Diseases: immunology (MeSH) ; Kidney Diseases: pathology (MeSH) ; Membrane Proteins (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Inbred NOD (MeSH) ; Mice, Knockout (MeSH) ; Monocytes: immunology (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: immunology (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; Toll-Like Receptor 2: metabolism (MeSH) ; Toll-Like Receptor 4: metabolism (MeSH) ; APOC3 protein, human ; Adaptor Proteins, Signal Transducing ; Apolipoprotein C-III ; Inflammasomes ; Membrane Proteins ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human ; Reactive Oxygen Species ; SCIMP protein, human ; TLR2 protein, human ; TLR4 protein, human ; Toll-Like Receptor 2 ; Toll-Like Receptor 4 ; Caspase 8

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Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz ; AG Latz)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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