Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation

被引：0

作者：

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

机构：

[1] Saarland University,Department of Internal Medicine IV (Nephrology and Hypertension)

[2] Rush University Medical Center,Department of Internal Medicine

[3] RWTH Aachen University Hospital,Institute for Molecular Cardiovascular Research

[4] Saarland University,Molecular Biophysics, Center of Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine

[5] RWTH Aachen University Hospital,Department of Nephrology

[6] Erasmus Medical Center,Division of Nephrology and Transplantation, Department of Internal Medicine

[7] Saarland University,Institute for Clinical and Experimental Surgery

[8] Saarland University,Department of Internal Medicine III (Cardiology)

[9] University Hospital Leipzig,Department of Cardiology

[10] Medical University of Graz,Department of Internal Medicine, Division of Angiology

[11] Saarland University,Department of Transplant and Infection Immunology

[12] Saarland University,Department of Internal Medicine I (Oncology, Hematology, Clinical Immunology and Rheumatology)

[13] Saarland University,Department of Internal Medicine V (Pneumology and Intensive Care Medicine)

[14] Medical University of Graz,Molecular Biology and Biochemistry, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

[15] RWTH Aachen University Hospital,Biointerface Laboratory

[16] University Hospital Zurich,Institute of Clinical Chemistry

[17] University of Heidelberg,Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Mannheim Medical Faculty

[18] Synlab Holding Deutschland,Synlab Academy

[19] Medical University of Graz,Clinical Institute of Medical and Chemical Laboratory Diagnostics

[20] University of Maastricht,CARIM School for Cardiovascular Diseases

[21] ETH,Institute of Molecular Health Science

[22] Bonn University,Institute of Innate Immunity

[23] University of Massachusetts Medical School,Division of Infectious Diseases and Immunology, Department of Medicine

[24] German Center of Neurodegenerative Diseases (DZNE),undefined

来源：

Nature Immunology | 2020年 / 21卷

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摘要：

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.

引用

页码：30 / 41

页数：11

共 95 条

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