Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.,Nature Immunology

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Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.
Nature Immunology ( IF 27.7 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41590-019-0548-1
Stephen Zewinger ₁ , Jochen Reiser ₂ , Vera Jankowski ₃ , Dalia Alansary ₄ , Eunsil Hahm ₂ , Sarah Triem ₁ , Mira Klug ₁ , Stefan J Schunk ₁ , David Schmit ₁ , Rafael Kramann _{5,

6} , Christina Körbel ₇ , Emmanuel Ampofo ₇ , Matthias W Laschke ₇ , Simina-Ramona Selejan ₈ , Anna Paschen ₁ , Tobias Herter ₁ , Susanne Schuster ₉ , Günther Silbernagel ₁₀ , Martina Sester ₁₁ , Urban Sester ₁ , Gunter Aßmann ₁₂ , Robert Bals ₁₃ , Gerhard Kostner ₁₄ , Willi Jahnen-Dechent ₁₅ , Michael D Menger ₇ , Lucia Rohrer ₁₆ , Winfried März _{17,

18,

19} , Michael Böhm ₈ , Joachim Jankowski _{3,

20} , Manfred Kopf ₂₁ , Eicke Latz _{22,

23,

24} , Barbara A Niemeyer ₄ , Danilo Fliser ₁ , Ulrich Laufs ₉ , Thimoteus Speer ₁

Affiliation

Department of Internal Medicine IV (Nephrology and Hypertension), Saarland University, Homburg, Germany.
Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany.
Molecular Biophysics, Center of Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland University, Homburg, Germany.
Department of Nephrology, RWTH Aachen University Hospital, Aachen, Germany.
Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany.
Department of Internal Medicine III (Cardiology), Saarland University, Homburg, Germany.
Department of Cardiology, University Hospital Leipzig, Leipzig, Germany.
Department of Internal Medicine, Division of Angiology, Medical University of Graz, Graz, Austria.
Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.
Department of Internal Medicine I (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University, Homburg, Germany.
Department of Internal Medicine V (Pneumology and Intensive Care Medicine), Saarland University, Homburg, Germany.
Molecular Biology and Biochemistry, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
Biointerface Laboratory, RWTH Aachen University Hospital, Aachen, Germany.
Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
Synlab Academy, Synlab Holding Deutschland, Mannheim, Germany.
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
CARIM School for Cardiovascular Diseases, University of Maastricht, Maastricht, the Netherlands.
Institute of Molecular Health Science, ETH, Zurich, Switzerland.
Institute of Innate Immunity, Bonn University, Bonn, Germany.
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
German Center of Neurodegenerative Diseases (DZNE), Bonn, Germany.

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.

中文翻译：

载脂蛋白 C3 通过替代性炎性体激活诱导炎症和器官损伤。

NLRP3 炎性体驱动的炎症参与多种疾病的发病机制。鉴定内源性炎性体激活剂对于开发新的抗炎治疗策略至关重要。在这里，我们发现载脂蛋白 C3 (ApoC3) 通过 caspase-8 和 Toll 样受体 2 和 4 的二聚化诱导替代 NLRP3 炎性体，从而激活人单核细胞中的 NLRP3 炎性体。人单核细胞中的替代性炎性体激活由 Toll-像受体衔接蛋白 SCIMP。这会触发 Lyn/Syk 依赖性钙进入和活性氧的产生，从而导致 caspase-8 的激活。在人源化小鼠模型中，ApoC3 在体内激活人单核细胞以阻碍内皮再生并以 NLRP3 和 caspase-8 依赖性方式促进肾损伤。这些数据为 NLRP3 炎性体的调节和含有 ApoC3 的富含甘油三酯的脂蛋白的病理生理学作用提供了新的见解。靶向 ApoC3 可能会防止器官损伤，并为血管和肾脏疾病提供抗炎治疗。

更新日期：2019-12-11

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