2. Academic Validation
  3. Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

  • J Am Coll Cardiol. 2018 Feb 6;71(5):527-542. 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 23
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.
  • 3 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.
  • 4 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
  • 5 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
  • 6 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.
  • 7 Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
  • 8 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany.
  • 9 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
  • 10 Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 11 Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, the Netherlands.
  • 12 German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
  • 13 Bioceros BV, Utrecht, the Netherlands.
  • 14 Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 15 Bioceros BV, Utrecht, the Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 16 Department of Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 17 Centre for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, Nijmegen, the Netherlands.
  • 18 Division of Cardiology, Department of Medicine, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York.
  • 19 Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
  • 20 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 21 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.
  • 22 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.
  • 23 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. Electronic address: E.Lutgens@amc.uva.nl.
PMID: 29406859 DOI: 10.1016/j.jacc.2017.11.055
Abstract

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.

Keywords

atherosclerosis; drug development; immunology; inflammation; nanotechnology.

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