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

Bosmans, Laura A.; van Tiel, Claudia M.; Aarts, Suzanne A.B.M.; Willemsen, Lisa; Baardman, Jeroen; van Os, Bram W.; den Toom, Myrthe; Beckers, Linda; Ahern, David J.; Levels, Johannes H.M.; Jongejan, Aldo; Moerland, Perry D.; Verberk, Sanne G.S.; van den Bossche, Jan; de Winther, Menno M.P.J.; Weber, Christian; Atzler, Dorothee; Monaco, Claudia; Gerdes, Norbert; Shami, Annelie; Lutgens, Esther

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

Mark

Bosmans, Laura A. ; van Tiel, Claudia M. ; Aarts, Suzanne A.B.M. ; Willemsen, Lisa ; Baardman, Jeroen ; van Os, Bram W. ; den Toom, Myrthe ; Beckers, Linda ; Ahern, David J. and Levels, Johannes H.M. , et al. (2023) In Cardiovascular Research 119(5). p.1146-1160

Abstract: 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 Cd40^flox/flox and LysM-cre Cd40^flox/flox mice on an Apoe^−/− background were generated (CD40^wt and CD40^mac−/− , respect-Results... (More); 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 Cd40^flox/flox and LysM-cre Cd40^flox/flox mice on an Apoe^−/− background were generated (CD40^wt and CD40^mac−/− , respect-Results ively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40^mac−/− compared to CD40^wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40^mac−/− 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 CD40^mac−/− compared to CD40^wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40^mac−/− 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.
(Less)

Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/dad2bb00-7656-4bf7-9e1e-c93bc6ee01ad

author

Bosmans, Laura A. ; van Tiel, Claudia M. ; Aarts, Suzanne A.B.M. ; Willemsen, Lisa ; Baardman, Jeroen ; van Os, Bram W. ; den Toom, Myrthe ; Beckers, Linda ; Ahern, David J. and Levels, Johannes H.M. , et al. (More)

Bosmans, Laura A. ; van Tiel, Claudia M. ; Aarts, Suzanne A.B.M. ; Willemsen, Lisa ; Baardman, Jeroen ; van Os, Bram W. ; den Toom, Myrthe ; Beckers, Linda ; Ahern, David J. ; Levels, Johannes H.M. ; Jongejan, Aldo ; Moerland, Perry D. ; Verberk, Sanne G.S. ; van den Bossche, Jan ; de Winther, Menno M.P.J. ; Weber, Christian ; Atzler, Dorothee ; Monaco, Claudia ; Gerdes, Norbert ; Shami, Annelie ^LU

and Lutgens, Esther (Less)

organization

publishing date

2023-05-01

type

Contribution to journal

publication status

published

subject

Cardiac and Cardiovascular Systems

keywords

Atherosclerosis, CD40, Inflammation, Macrophage

in

Cardiovascular Research

volume

119

issue

5

pages

15 pages

publisher

Oxford University Press

external identifiers

pmid:35587037
scopus:85140589978

ISSN

0008-6363

DOI

10.1093/cvr/cvac084

language

English

LU publication?

yes

additional info

Funding Information: This work was 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). This work was also supported by The Swedish Research Council (2015-00497) and The Swedish Hearth and Lung Foundation [20140206; 20150325], the Deutsche Forschungs Gemeinschaft (SFB 1123 to E.L., C.W., and D.A.; TRR259 to E.L. and N.G.; SFB1116 to N.G.) and The European Research Council (ERC Consolidator grant to E.L.). Funding Information: 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. Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

id

dad2bb00-7656-4bf7-9e1e-c93bc6ee01ad

date added to LUP

2024-01-11 14:16:48

date last changed

2024-04-26 11:05:39

@article{dad2bb00-7656-4bf7-9e1e-c93bc6ee01ad,
  abstract     = {{<p>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 Cd40<sup>flox/flox</sup> and LysM-cre Cd40<sup>flox/flox</sup> mice on an Apoe<sup>−/−</sup> background were generated (CD40<sup>wt</sup> and CD40<sup>mac−/−</sup> , respect-Results ively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40<sup>mac−/−</sup> compared to CD40<sup>wt</sup> mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40<sup>mac−/−</sup> 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<sup>+</sup>CD209b<sup>−</sup> macrophages in the atherosclerotic aorta of CD40<sup>mac−/−</sup> compared to CD40<sup>wt</sup> mice. RNA-sequencing of bone marrow-derived macrophages of CD40<sup>mac−/−</sup> 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.</p>}},
  author       = {{Bosmans, Laura A. and van Tiel, Claudia M. and Aarts, Suzanne A.B.M. and Willemsen, Lisa and Baardman, Jeroen and van Os, Bram W. and den Toom, Myrthe and Beckers, Linda and Ahern, David J. and Levels, Johannes H.M. and Jongejan, Aldo and Moerland, Perry D. and Verberk, Sanne G.S. and van den Bossche, Jan and de Winther, Menno M.P.J. and Weber, Christian and Atzler, Dorothee and Monaco, Claudia and Gerdes, Norbert and Shami, Annelie and Lutgens, Esther}},
  issn         = {{0008-6363}},
  keywords     = {{Atherosclerosis; CD40; Inflammation; Macrophage}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{1146--1160}},
  publisher    = {{Oxford University Press}},
  series       = {{Cardiovascular Research}},
  title        = {{Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages’ transition into a pro-inflammatory state}},
  url          = {{http://dx.doi.org/10.1093/cvr/cvac084}},
  doi          = {{10.1093/cvr/cvac084}},
  volume       = {{119}},
  year         = {{2023}},
}

Lund University Publications

LUND UNIVERSITY LIBRARIES

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