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Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death.
Seijkens, Tom T P; Poels, Kikkie; Meiler, Svenja; van Tiel, Claudia M; Kusters, Pascal J H; Reiche, Myrthe; Atzler, Dorothee; Winkels, Holger; Tjwa, Marc; Poelman, Hessel; Slütter, Bram; Kuiper, Johan; Gijbels, Marion; Kuivenhoven, Jan Albert; Matic, Ljubica Perisic; Paulsson-Berne, Gabrielle; Hedin, Ulf; Hansson, Göran K; Nicolaes, Gerry A F; Daemen, Mat J A P; Weber, Christian; Gerdes, Norbert; de Winther, Menno P J; Lutgens, Esther.
Afiliação
  • Seijkens TTP; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Poels K; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Pettenkoferstraße 8a & 9, Munich, Germany.
  • Meiler S; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • van Tiel CM; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Kusters PJH; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Reiche M; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Atzler D; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Winkels H; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Pettenkoferstraße 8a & 9, Munich, Germany.
  • Tjwa M; Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Goethestraße 33D, Munich, Germany.
  • Poelman H; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Pettenkoferstraße 8a & 9, Munich, Germany.
  • Slütter B; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Pettenkoferstraße 8a & 9, Munich, Germany.
  • Kuiper J; Laboratory of Vascular Hematology/Angiogenesis, Institute for Transfusion Medicine, Goethe University Frankfurt, Sandhofstraße 1D, Germany.
  • Gijbels M; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Kuivenhoven JA; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER, Maastricht University, Maastricht, the Netherlands.
  • Matic LP; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einstein weg 55, 2333 CC, Leiden, the Netherlands.
  • Paulsson-Berne G; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einstein weg 55, 2333 CC, Leiden, the Netherlands.
  • Hedin U; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Hansson GK; Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, Postbus 72, AB Groningen, The Netherlands.
  • Nicolaes GAF; Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Solna, SE-171 76, Stockholm, Sweden.
  • Daemen MJAP; Department of Medicine and Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Solna SE-171 76 Stockholm, Sweden.
  • Weber C; Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Solna, SE-171 76, Stockholm, Sweden.
  • Gerdes N; Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Solna, SE-171 76, Stockholm, Sweden.
  • de Winther MPJ; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Room K1-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
  • Lutgens E; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER, Maastricht University, Maastricht, the Netherlands.
Eur Heart J ; 40(4): 372-382, 2019 01 21.
Article em En | MEDLINE | ID: mdl-30452556
Aims: The E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis. Methods and results: The expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb-/-Apoe-/- mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8+ T cells. Cblb-/-Apoe-/- macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8+ T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFNγ and granzyme B production was enhanced in Cblb-/-Apoe-/- CD8+ T cells, which provoked macrophage killing. Depletion of CD8+ T cells in Cblb-/-Apoe-/- bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8+ T cells. Conclusion: Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8+ T cell activation and CD8+ T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma de Células B / Linfócitos T CD8-Positivos / Aterosclerose / Proteína Oncogênica v-cbl / Placa Aterosclerótica / Macrófagos Limite: Animals / Humans Idioma: En Revista: Eur Heart J Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma de Células B / Linfócitos T CD8-Positivos / Aterosclerose / Proteína Oncogênica v-cbl / Placa Aterosclerótica / Macrófagos Limite: Animals / Humans Idioma: En Revista: Eur Heart J Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Holanda