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 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

doi:10.1038/s41590-019-0548-1

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 Körbel, Emmanuel Ampofo, Matthias W. Laschke, Simina Ramona Selejan, Anna Paschen, Tobias Herter, Susanne Schuster, Günther Silbernagel, Martina Sester, Urban SesterGunter 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

Research output: Contribution to journal › Article › peer-review

189 Scopus citations

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 language	English (US)
Pages (from-to)	30-41
Number of pages	12
Journal	Nature Immunology
Volume	21
Issue number	1
DOIs	https://doi.org/10.1038/s41590-019-0548-1
State	Published - Jan 1 2020
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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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., ... Speer, T. (2020). Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nature Immunology, 21(1), 30-41. https://doi.org/10.1038/s41590-019-0548-1

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 2020, 'Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation', Nature Immunology, vol. 21, no. 1, pp. 30-41. https://doi.org/10.1038/s41590-019-0548-1

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title = "Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation",

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.",

author = "Stephen Zewinger and Jochen Reiser and Vera Jankowski and Dalia Alansary and Eunsil Hahm and Sarah Triem and Mira Klug and Schunk, {Stefan J.} and David Schmit and Rafael Kramann and Christina K{\"o}rbel and Emmanuel Ampofo and Laschke, {Matthias W.} and Selejan, {Simina Ramona} and Anna Paschen and Tobias Herter and Susanne Schuster and G{\"u}nther Silbernagel and Martina Sester and Urban Sester and Gunter A{\ss}mann and Robert Bals and Gerhard Kostner and Willi Jahnen-Dechent and Menger, {Michael D.} and Lucia Rohrer and Winfried M{\"a}rz and Michael B{\"o}hm and Joachim Jankowski and Manfred Kopf and Eicke Latz and Niemeyer, {Barbara A.} and Danilo Fliser and Ulrich Laufs and Thimoteus Speer",

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AU - Zewinger, Stephen

AU - Reiser, Jochen

AU - Jankowski, Vera

AU - Alansary, Dalia

AU - Hahm, Eunsil

AU - Triem, Sarah

AU - Klug, Mira

AU - Schunk, Stefan J.

AU - Schmit, David

AU - Kramann, Rafael

AU - Körbel, Christina

AU - Ampofo, Emmanuel

AU - Laschke, Matthias W.

AU - Selejan, Simina Ramona

AU - Paschen, Anna

AU - Herter, Tobias

AU - Schuster, Susanne

AU - Silbernagel, Günther

AU - Sester, Martina

AU - Sester, Urban

AU - Aßmann, Gunter

AU - Bals, Robert

AU - Kostner, Gerhard

AU - Jahnen-Dechent, Willi

AU - Menger, Michael D.

AU - Rohrer, Lucia

AU - März, Winfried

AU - Böhm, Michael

AU - Jankowski, Joachim

AU - Kopf, Manfred

AU - Latz, Eicke

AU - Niemeyer, Barbara A.

AU - Fliser, Danilo

AU - Laufs, Ulrich

AU - Speer, Thimoteus

PY - 2020/1/1

Y1 - 2020/1/1

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Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation

Abstract

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