Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state.

Autor:	Bosmans LA; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., van Tiel CM; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Aarts SABM; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Willemsen L; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Baardman J; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., van Os BW; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Toom MD; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Beckers L; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Ahern DJ; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Levels JHM; Department of Vascular Medicine, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Jongejan A; Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands., Moerland PD; Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands., Verberk SGS; Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands., den Bossche JV; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.; Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands., de Winther MMPJ; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands., Weber C; Institute of Cardiovascular Prevention (IPEK), Ludwig Maximilian's 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.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Atzler D; Institute of Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Walter-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität, München, Germany., Monaco C; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Gerdes N; Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Hospital and Heinrich Heine University Düsseldorf, Germany., Shami A; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.; Department of Clinical Sciences Malmö, Lund University, Clinical Research Center, Malmö, Sweden., Lutgens E; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) & Amsterdam Infection and Immunity (AII), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.; Institute of Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany.; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.; Experimental Cardiovascular Immunology Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 May 22; Vol. 119 (5), pp. 1146-1160.
DOI:	10.1093/cvr/cvac084
Abstrakt:	Aims: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. Method and Results: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac-/- compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). Conclusions: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis. Competing Interests: Conflicts of interest: C.W., D.A., E.L. and N.G. are supported by the Deutsche Forschungs Gemeinschaft (grants CRC1123, A5, SFB 1123, TRR259, SFB1116). E.L is also supported by the Netherlands CardioVascular Research Initiative, the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences’ for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19), and the ERC Con grant (CD40-INN). E.L. is also the vice chair at the ESC working group on atherosclerosis, serves on the EAS programme committee and the ATVB awards and programme committee and has received payment or honoraria for lectures at Novartis and Novo Nordisk. The remaining authors have nothing to disclose. (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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