靶向巨噬细胞中 CD40 诱导的 TRAF6 信号传导可减少动脉粥样硬化,Journal of the American College of Cardiology

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靶向巨噬细胞中 CD40 诱导的 TRAF6 信号传导可减少动脉粥样硬化
Journal of the American College of Cardiology ( IF 21.7 ) Pub Date : 2018-02-01 , DOI: 10.1016/j.jacc.2017.11.055
Tom T P Seijkens ₁ , Claudia M van Tiel ₂ , Pascal J H Kusters ₂ , Dorothee Atzler ₃ , Oliver Soehnlein ₄ , Barbara Zarzycka ₅ , Suzanne A B M Aarts ₂ , Marnix Lameijer ₂ , Marion J Gijbels ₆ , Linda Beckers ₂ , Myrthe den Toom ₂ , Bram Slütter ₇ , Johan Kuiper ₇ , Johan Duchene ₈ , Maria Aslani ₈ , Remco T A Megens ₉ , Cornelis van 't Veer ₁₀ , Gijs Kooij ₁₁ , Roy Schrijver ₁₂ , Marten A Hoeksema ₂ , Louis Boon ₁₃ , Francois Fay ₁₄ , Jun Tang ₁₅ , Samantha Baxter ₁₄ , Aldo Jongejan ₁₆ , Perry D Moerland ₁₆ , Gert Vriend ₁₇ , Boris Bleijlevens ₂ , Edward A Fisher ₁₈ , Raphael Duivenvoorden ₁₉ , Norbert Gerdes ₂₀ , Menno P J de Winther ₁ , Gerry A Nicolaes ₅ , Willem J M Mulder ₂₁ , Christian Weber ₂₂ , Esther Lutgens ₁

Affiliation

Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany.
Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.
Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; Walther-Straub-Institut for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, the Netherlands.
German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
Bioceros BV, Utrecht, the Netherlands.
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Bioceros BV, Utrecht, the Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Centre for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, Nijmegen, the Netherlands.
Division of Cardiology, Department of Medicine, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

背景破坏共刺激 CD40-CD40L 双联体可减少动脉粥样硬化，但会导致免疫抑制。作者最近发现了小分子抑制剂，可阻断 CD40 与肿瘤坏死因子受体相关因子 (TRAF) 6 (TRAF-STOPs) 之间的相互作用，同时保持 CD40-TRAF2/3/5 相互作用完整，从而保持 CD40 介导的免疫。目的本研究评估了 TRAF-STOP 治疗动脉粥样硬化的潜力。方法在载脂蛋白 E 缺陷 (Apoe-/-) 小鼠中研究了 TRAF-STOPs 对动脉粥样硬化的影响。重组高密度脂蛋白 (rHDL) 纳米颗粒用于将 TRAF-STOPs 靶向巨噬细胞。结果 TRAF-STOP 治疗年轻的 Apoe-/- 小鼠通过减少经典单核细胞中 CD40 和整合素的表达来减少动脉粥样硬化，从而阻碍单核细胞的募集。当患有动脉粥样硬化的 Apoe-/- 小鼠接受 TRAF-STOP 治疗时，斑块进展停止，斑块中胶原蛋白增加，出现小坏死核心，并且仅包含少数免疫细胞。TRAF-STOP 治疗不会损害 CD40 的“经典”免疫途径，包括 T 细胞增殖和共刺激、Ig 同种型转换或生发中心形成，但会降低炎症单核细胞中 CD40 和 β2-整合素的表达。体外测试和转录分析表明，TRAF-STOPs 可有效减少巨噬细胞迁移和活化，这可能归因于经典 NF-κB 通路信号中间体的磷酸化减少。为了将 TRAF-STOPs 专门针对巨噬细胞，TRAF-STOP 6877002 被纳入 rHDL 纳米粒子。六周的 rHDL-6877002 治疗减弱了 Apoe-/- 小鼠动脉粥样硬化的发生。结论 TRAF-STOPs 可以克服目前长期 CD40 抑制动脉粥样硬化的局限性，并有可能成为未来动脉粥样硬化的治疗方法。

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Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

Background Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. Objectives This study evaluates the potential of TRAF-STOP treatment in atherosclerosis. Methods The effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe−/−) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages. Results TRAF-STOP treatment of young Apoe−/− mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe−/− mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair “classical” immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and β2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-κB pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe−/− mice. Conclusions TRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis.

更新日期：2018-02-01

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