1. Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis
- Author
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Claudia M. van Tiel, Roy Schrijver, Dorothee Atzler, Aldo Jongejan, Oliver Soehnlein, Marnix Lameijer, Menno P.J. de Winther, Francois Fay, Suzanne A. B. M. Aarts, Barbara Zarzycka, Bram Slütter, Christian Weber, Jun Tang, Perry D. Moerland, Norbert Gerdes, Boris Bleijlevens, Myrthe den Toom, Raphaël Duivenvoorden, Esther Lutgens, Tom Seijkens, Linda Beckers, Pascal J. H. Kusters, Remco T. A. Megens, Marion J.J. Gijbels, Gijs Kooij, Cornelis van 't Veer, Johan Kuiper, Gerry A. F. Nicolaes, Gert Vriend, Louis Boon, Edward A. Fisher, Willem J. M. Mulder, Samantha Baxter, Johan Duchene, Maria Aslani, Marten A. Hoeksema, Biomedische Technologie, Promovendi CD, Biochemie, Moleculaire Genetica, Pathologie, RS: CARIM - R3.06 - The vulnerable plaque: makers and markers, RS: CARIM - R2.06 - Intermediate cardiac metabolism, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, RS: CARIM - R1.01 - Blood proteins & engineering, Medical Biochemistry, ACS - Amsterdam Cardiovascular Sciences, Graduate School, Other departments, Center of Experimental and Molecular Medicine, APH - Methodology, Epidemiology and Data Science, APH - Personalized Medicine, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Other Research, Nephrology, ACS - Atherosclerosis & ischemic syndromes, ACS - Pulmonary hypertension & thrombosis, Molecular cell biology and Immunology, and Amsterdam Neuroscience - Neuroinfection & -inflammation
- Subjects
0301 basic medicine ,Apolipoprotein E ,MECHANISM ,rHDL, recombinant high-density lipoprotein ,Cell Culture Techniques ,030204 cardiovascular system & hematology ,PHENOTYPE ,THERAPY ,Monocytes ,ACTIVATION ,immunology ,Mice ,DC, dendritic cell ,0302 clinical medicine ,Cell Movement ,TRAF, tumor necrosis factor receptor-associated factor ,CD40 ,Medicine ,Propiophenones ,Aniline Compounds ,biology ,nanotechnology ,NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells ,BMDM, bone marrow-derived macrophage ,Plaque, Atherosclerotic ,3. Good health ,medicine.anatomical_structure ,Apoe, apolipoprotein E ,Tumor necrosis factor alpha ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,CD40-TRAF6 INTERACTIONS ,Signal Transduction ,Bioinformatics ,CD40 Ligand ,INHIBITION ,Inflammation ,CVD, cardiovascular disease ,Article ,03 medical and health sciences ,Immune system ,Animals ,Humans ,TNF Receptor-Associated Factor 6 ,SMI, small molecule inhibitor ,business.industry ,Monocyte ,Macrophages ,Germinal center ,drug development ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Immunoglobulin class switching ,inflammation ,CELLS ,Cancer research ,biology.protein ,IMMUNE-SYSTEM ,atherosclerosis ,business ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - 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., Central Illustration
- Published
- 2018
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