Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

Tom T. P. Seijkens; Claudia M. van Tiel; Pascal J. H. Kusters; Dorothee Atzler; Oliver Soehnlein; Barbara Zarzycka; Suzanne A. B. M. Aarts; Marnix Lameijer; Marion J. Gijbels; Linda Beckers; Myrthe den Toom; Bram Slutter; Johan Kuiper; Johan Duchene; Maria Aslani; Remco T. A. Megens; Cornelis van 't Veer; Gijs Kooij; Roy Schrijver; Marten A. Hoeksema; Louis Boon; Francois Fay; Jun Tang; Samantha Baxter; Aldo Jongejan; Perry D. Moerland; Gert Vriend; Boris Bleijlevens; Edward A. Fisher; Raphael Duivenvoorden; Norbert Gerdes; Menno P. J. de Winther; Gerry A. Nicolaes; Willem J. M. Mulder; Christian Weber; Esther Lutgens

doi:10.1016/j.jacc.2017.11.055

Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

Tom T. P. Seijkens, Claudia M. van Tiel, Pascal J. H. Kusters, Dorothee Atzler, Oliver Soehnlein, Barbara Zarzycka, Suzanne A. B. M. Aarts, Marnix Lameijer, Marion J. Gijbels, Linda Beckers, Myrthe den Toom, Bram Slutter, Johan Kuiper, Johan Duchene, Maria Aslani, Remco T. A. Megens, Cornelis van 't Veer, Gijs Kooij, Roy Schrijver, Marten A. HoeksemaLouis Boon, Francois Fay, Jun Tang, Samantha Baxter, Aldo Jongejan, Perry D. Moerland, Gert Vriend, Boris Bleijlevens, Edward A. Fisher, Raphael Duivenvoorden, Norbert Gerdes, Menno P. J. de Winther, Gerry A. Nicolaes, Willem J. M. Mulder, Christian Weber, Esther Lutgens^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 beta 2-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-kappa B 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. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Original language	English
Pages (from-to)	527-542
Number of pages	16
Journal	Journal of the American College of Cardiology
Volume	71
Issue number	5
DOIs	https://doi.org/10.1016/j.jacc.2017.11.055
Publication status	Published - 6 Feb 2018

Keywords

atherosclerosis
drug development
immunology
inflammation
nanotechnology
CD40-TRAF6 INTERACTIONS
IMMUNE-SYSTEM
MICE
CD40
INHIBITION
CELLS
ACTIVATION
PHENOTYPE
MECHANISM
THERAPY

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Seijkens, T. T. P., van Tiel, C. M., Kusters, P. J. H., Atzler, D., Soehnlein, O., Zarzycka, B., Aarts, S. A. B. M., Lameijer, M., Gijbels, M. J., Beckers, L., den Toom, M., Slutter, B., Kuiper, J., Duchene, J., Aslani, M., Megens, R. T. A., van 't Veer, C., Kooij, G., Schrijver, R., ... Lutgens, E. (2018). Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. Journal of the American College of Cardiology, 71(5), 527-542. https://doi.org/10.1016/j.jacc.2017.11.055

@article{70a5dc4371fb4ede8bfc4db03d502fec,

title = "Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis",

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 beta 2-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-kappa B 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. Published by Elsevier on behalf of the American College of Cardiology Foundation.",

keywords = "atherosclerosis, drug development, immunology, inflammation, nanotechnology, CD40-TRAF6 INTERACTIONS, IMMUNE-SYSTEM, MICE, CD40, INHIBITION, CELLS, ACTIVATION, PHENOTYPE, MECHANISM, THERAPY",

author = "Seijkens, \{Tom T. P.\} and \{van Tiel\}, \{Claudia M.\} and Kusters, \{Pascal J. H.\} and Dorothee Atzler and Oliver Soehnlein and Barbara Zarzycka and Aarts, \{Suzanne A. B. M.\} and Marnix Lameijer and Gijbels, \{Marion J.\} and Linda Beckers and \{den Toom\}, Myrthe and Bram Slutter and Johan Kuiper and Johan Duchene and Maria Aslani and Megens, \{Remco T. A.\} and \{van 't Veer\}, Cornelis and Gijs Kooij and Roy Schrijver and Hoeksema, \{Marten A.\} and Louis Boon and Francois Fay and Jun Tang and Samantha Baxter and Aldo Jongejan and Moerland, \{Perry D.\} and Gert Vriend and Boris Bleijlevens and Fisher, \{Edward A.\} and Raphael Duivenvoorden and Norbert Gerdes and \{de Winther\}, \{Menno P. J.\} and Nicolaes, \{Gerry A.\} and Mulder, \{Willem J. M.\} and Christian Weber and Esther Lutgens",

year = "2018",

month = feb,

day = "6",

doi = "10.1016/j.jacc.2017.11.055",

language = "English",

volume = "71",

pages = "527--542",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

number = "5",

}

Seijkens, TTP, van Tiel, CM, Kusters, PJH, Atzler, D, Soehnlein, O, Zarzycka, B, Aarts, SABM, Lameijer, M, Gijbels, MJ, Beckers, L, den Toom, M, Slutter, B, Kuiper, J, Duchene, J, Aslani, M, Megens, RTA, van 't Veer, C, Kooij, G, Schrijver, R, Hoeksema, MA, Boon, L, Fay, F, Tang, J, Baxter, S, Jongejan, A, Moerland, PD, Vriend, G, Bleijlevens, B, Fisher, EA, Duivenvoorden, R, Gerdes, N, de Winther, MPJ, Nicolaes, GA, Mulder, WJM, Weber, C & Lutgens, E 2018, 'Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis', Journal of the American College of Cardiology, vol. 71, no. 5, pp. 527-542. https://doi.org/10.1016/j.jacc.2017.11.055

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 - Slutter, 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 beta 2-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-kappa B 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. Published by Elsevier on behalf of the American College of Cardiology Foundation.

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 beta 2-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-kappa B 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. Published by Elsevier on behalf of the American College of Cardiology Foundation.

KW - atherosclerosis

KW - drug development

KW - immunology

KW - inflammation

KW - nanotechnology

KW - CD40-TRAF6 INTERACTIONS

KW - IMMUNE-SYSTEM

KW - MICE

KW - CD40

KW - INHIBITION

KW - CELLS

KW - ACTIVATION

KW - PHENOTYPE

KW - MECHANISM

KW - THERAPY

U2 - 10.1016/j.jacc.2017.11.055

DO - 10.1016/j.jacc.2017.11.055

M3 - Article

C2 - 29406859

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 -

Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis

Abstract

Keywords

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