TY - JOUR
T1 - Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis
AU - Seijkens, Tom T.P.
AU - van Tiel, Claudia M.
AU - Kusters, Pascal J.H.
AU - Atzler, Dorothee
AU - Soehnlein, Oliver
AU - Zarzycka, Barbara
AU - Aarts, Suzanne A.B.M.
AU - Lameijer, Marnix
AU - Gijbels, Marion J.
AU - Beckers, Linda
AU - den Toom, Myrthe
AU - Slütter, Bram
AU - Kuiper, Johan
AU - Duchene, Johan
AU - Aslani, Maria
AU - Megens, Remco T.A.
AU - van ‘t Veer, Cornelis
AU - Kooij, Gijs
AU - Schrijver, Roy
AU - Hoeksema, Marten A.
AU - Boon, Louis
AU - Fay, Francois
AU - Tang, Jun
AU - Baxter, Samantha
AU - Jongejan, Aldo
AU - Moerland, Perry D.
AU - Vriend, Gert
AU - Bleijlevens, Boris
AU - Fisher, Edward A.
AU - Duivenvoorden, Raphael
AU - Gerdes, Norbert
AU - de Winther, Menno P.J.
AU - Nicolaes, Gerry A.
AU - Mulder, Willem J.M.
AU - Weber, Christian
AU - Lutgens, Esther
PY - 2018/2/6
Y1 - 2018/2/6
N2 - 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.
AB - 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.
KW - atherosclerosis
KW - drug development
KW - immunology
KW - inflammation
KW - nanotechnology
UR - http://www.scopus.com/inward/record.url?scp=85044860735&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044860735&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2017.11.055
DO - 10.1016/j.jacc.2017.11.055
M3 - Article
C2 - 29406859
AN - SCOPUS:85044860735
SN - 0735-1097
VL - 71
SP - 527
EP - 542
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 5
ER -