Related Experiment Video
Updated: Feb 14, 2026
Synthesis of Monocyte-targeting Peptide Amphiphile Micelles for Imaging of Atherosclerosis
Published on: November 17, 2017
Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis
Tom T P Seijkens1, Claudia M van Tiel2, Pascal J H Kusters2
1Department 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.
Insights
New TRAF-STOP treatments targeting CD40 interactions show promise for atherosclerosis. These inhibitors reduce inflammation and plaque progression without suppressing essential immune functions, offering a potential new therapy.
Area of Science:
- Immunology
- Cardiovascular Research
- Pharmacology
Background:
- Disrupting the CD40-CD40L pathway can reduce atherosclerosis but may cause immune suppression.
- Tumor necrosis factor receptor-associated factor (TRAF)-STOPs selectively inhibit CD40-TRAF6 interaction, preserving other CD40-mediated immune responses.
Purpose of the Study:
- To evaluate the therapeutic potential of TRAF-STOP treatment for atherosclerosis.
- To investigate the effects of TRAF-STOPs on atherosclerotic plaque development and immune cell function.
Main Methods:
- Apolipoprotein E deficient (Apoe-/-) mice were used to model atherosclerosis.
- Small molecule TRAF-STOPs were administered, some encapsulated in recombinant high-density lipoprotein (rHDL) nanoparticles for targeted delivery to macrophages.
- Effects on atherosclerotic plaques, immune cell expression (CD40, integrins), and immune pathways were analyzed.
Main Results:
- TRAF-STOP treatment reduced atherosclerosis in young mice by decreasing monocyte recruitment.
- In established atherosclerosis, TRAF-STOPs halted plaque progression, increased collagen, and reduced necrotic cores and immune cell infiltration.
- Immune pathways, including T-cell proliferation and antibody production, remained intact, while macrophage migration and activation were reduced.
Conclusions:
- TRAF-STOPs offer a novel therapeutic strategy for atherosclerosis by selectively modulating CD40 signaling.
- This approach overcomes limitations of broad CD40 inhibition, preserving immunity while combating atherosclerosis.
- TRAF-STOPs demonstrate significant potential as a future treatment for cardiovascular disease.
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.
Related Concept Videos
01:26Atherosclerosis III: Management
01:30Atherosclerosis I: Introduction
02:03What is Cell Signaling?
01:27Atherosclerosis II: Clinical Manifestations and Diagnostic Tests
01:18Reducing Line Loss
With a step-up transformer at the source, the voltage is increased, thereby reducing the current in the transmission lines since power loss in...
01:30Bacterial Signaling