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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Vydané v:	Journal of the American College of Cardiology Ročník 71; číslo 5; s. 527
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 06.02.2018
Predmet:	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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Abstract	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.
AbstractList	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.BACKGROUNDDisrupting 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.OBJECTIVESThis 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.METHODSThe 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.RESULTSTRAF-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.CONCLUSIONSTRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for 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-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.
Author	van Tiel, Claudia M Aarts, Suzanne A B M Kuiper, Johan de Winther, Menno P J Duchene, Johan Baxter, Samantha Kusters, Pascal J H Slütter, Bram Bleijlevens, Boris den Toom, Myrthe Seijkens, Tom T P Lameijer, Marnix Beckers, Linda Schrijver, Roy Boon, Louis Weber, Christian Lutgens, Esther Mulder, Willem J M Gerdes, Norbert Tang, Jun Aslani, Maria van 't Veer, Cornelis Duivenvoorden, Raphael Fisher, Edward A Gijbels, Marion J Megens, Remco T A Kooij, Gijs Fay, Francois Hoeksema, Marten A Atzler, Dorothee Vriend, Gert Zarzycka, Barbara Jongejan, Aldo Soehnlein, Oliver Moerland, Perry D Nicolaes, Gerry A
Author_xml	– sequence: 1 givenname: Tom T P surname: Seijkens fullname: Seijkens, Tom T P organization: Department 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 – sequence: 2 givenname: Claudia M surname: van Tiel fullname: van Tiel, Claudia M organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 3 givenname: Pascal J H surname: Kusters fullname: Kusters, Pascal J H organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 4 givenname: Dorothee surname: Atzler fullname: Atzler, Dorothee organization: Department 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; Walther-Straub-Institut for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany – sequence: 5 givenname: Oliver surname: Soehnlein fullname: Soehnlein, Oliver organization: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany – sequence: 6 givenname: Barbara surname: Zarzycka fullname: Zarzycka, Barbara organization: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands – sequence: 7 givenname: Suzanne A B M surname: Aarts fullname: Aarts, Suzanne A B M organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 8 givenname: Marnix surname: Lameijer fullname: Lameijer, Marnix organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 9 givenname: Marion J surname: Gijbels fullname: Gijbels, Marion J organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands – sequence: 10 givenname: Linda surname: Beckers fullname: Beckers, Linda organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 11 givenname: Myrthe surname: den Toom fullname: den Toom, Myrthe organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 12 givenname: Bram surname: Slütter fullname: Slütter, Bram organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands – sequence: 13 givenname: Johan surname: Kuiper fullname: Kuiper, Johan organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands – sequence: 14 givenname: Johan surname: Duchene fullname: Duchene, Johan organization: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany – sequence: 15 givenname: Maria surname: Aslani fullname: Aslani, Maria organization: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany – sequence: 16 givenname: Remco T A surname: Megens fullname: Megens, Remco T A organization: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands – sequence: 17 givenname: Cornelis surname: van 't Veer fullname: van 't Veer, Cornelis organization: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands – sequence: 18 givenname: Gijs surname: Kooij fullname: Kooij, Gijs organization: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, the Netherlands – sequence: 19 givenname: Roy surname: Schrijver fullname: Schrijver, Roy organization: German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany – sequence: 20 givenname: Marten A surname: Hoeksema fullname: Hoeksema, Marten A organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 21 givenname: Louis surname: Boon fullname: Boon, Louis organization: Bioceros BV, Utrecht, the Netherlands – sequence: 22 givenname: Francois surname: Fay fullname: Fay, Francois organization: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York – sequence: 23 givenname: Jun surname: Tang fullname: Tang, Jun organization: Bioceros BV, Utrecht, the Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York – sequence: 24 givenname: Samantha surname: Baxter fullname: Baxter, Samantha organization: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York – sequence: 25 givenname: Aldo surname: Jongejan fullname: Jongejan, Aldo organization: Department of Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands – sequence: 26 givenname: Perry D surname: Moerland fullname: Moerland, Perry D organization: Department of Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands – sequence: 27 givenname: Gert surname: Vriend fullname: Vriend, Gert organization: Centre for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, Nijmegen, the Netherlands – sequence: 28 givenname: Boris surname: Bleijlevens fullname: Bleijlevens, Boris organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands – sequence: 29 givenname: Edward A surname: Fisher fullname: Fisher, Edward A organization: Division of Cardiology, Department of Medicine, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York – sequence: 30 givenname: Raphael surname: Duivenvoorden fullname: Duivenvoorden, Raphael organization: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands – sequence: 31 givenname: Norbert surname: Gerdes fullname: Gerdes, Norbert organization: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany – sequence: 32 givenname: Menno P J surname: de Winther fullname: de Winther, Menno P J organization: Department 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 – sequence: 33 givenname: Gerry A surname: Nicolaes fullname: Nicolaes, Gerry A organization: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands – sequence: 34 givenname: Willem J M surname: Mulder fullname: Mulder, Willem J M organization: Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York – sequence: 35 givenname: Christian surname: Weber fullname: Weber, Christian organization: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands – sequence: 36 givenname: Esther surname: Lutgens fullname: Lutgens, Esther email: E.Lutgens@amc.uva.nl organization: Department 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. Electronic address: E.Lutgens@amc.uva.nl
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/29406859$$D View this record in MEDLINE/PubMed
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Keywords	atherosclerosis drug development nanotechnology inflammation immunology
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PublicationTitle	Journal of the American College of Cardiology
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References	29717214 - Nat Rev Cardiol. 2018 Jun;15(6):317 29406860 - J Am Coll Cardiol. 2018 Feb 6;71(5):543-546
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Snippet	Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule...
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SubjectTerms	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
Title	Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis
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