Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

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...

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Veröffentlicht in:Journal of the American College of Cardiology Jg. 71; H. 5; S. 527
Hauptverfasser: Seijkens, Tom T P, van Tiel, Claudia M, Kusters, Pascal J H, Atzler, Dorothee, Soehnlein, Oliver, Zarzycka, Barbara, Aarts, Suzanne A B M, Lameijer, Marnix, Gijbels, Marion J, Beckers, Linda, den Toom, Myrthe, Slütter, Bram, Kuiper, Johan, Duchene, Johan, Aslani, Maria, Megens, Remco T A, van 't Veer, Cornelis, Kooij, Gijs, Schrijver, Roy, Hoeksema, Marten A, Boon, Louis, Fay, Francois, Tang, Jun, Baxter, Samantha, Jongejan, Aldo, Moerland, Perry D, Vriend, Gert, Bleijlevens, Boris, Fisher, Edward A, Duivenvoorden, Raphael, Gerdes, Norbert, de Winther, Menno P J, Nicolaes, Gerry A, Mulder, Willem J M, Weber, Christian, Lutgens, Esther
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 06.02.2018
Schlagworte:
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
atherosclerosis
drug development
nanotechnology
inflammation
immunology
ISSN:1558-3597, 1558-3597
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Zusammenfassung: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. This study evaluates the potential of TRAF-STOP treatment in atherosclerosis. 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. 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. 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.
Bibliographie:ObjectType-Article-1
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ISSN:1558-3597
1558-3597
DOI:10.1016/j.jacc.2017.11.055