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
  • 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: [email protected].
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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