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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Atherosclerosis / pathology*
  • Atherosclerosis / prevention & control*
  • CD40 Ligand / antagonists & inhibitors*
  • Cell Culture Techniques
  • Cell Movement / drug effects
  • Disease Models, Animal
  • Humans
  • Macrophages / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / drug effects
  • Propiophenones / pharmacology
  • Signal Transduction / drug effects*
  • TNF Receptor-Associated Factor 6 / antagonists & inhibitors*


  • Aniline Compounds
  • Propiophenones
  • SMI 6860766
  • TNF Receptor-Associated Factor 6
  • CD40 Ligand