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

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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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 Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe−/− background were generated (CD40wt and CD40mac−/− , respect-Results ively). 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.

Originalspråkengelska
Sidor (från-till)1146-1160
Antal sidor15
TidskriftCardiovascular Research
Volym119
Nummer5
DOI
StatusPublished - 2023 maj 1

Bibliografisk information

Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Ämnesklassifikation (UKÄ)

  • Kardiologi

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