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

Cardiovasc Res. 2023 May 22;119(5):1146-1160. doi: 10.1093/cvr/cvac084.

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 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.

Keywords: Atherosclerosis; CD40; Inflammation; Macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / pathology
  • Atherosclerosis* / genetics
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / prevention & control
  • CD40 Antigens / genetics
  • Macrophages / metabolism
  • Mice
  • Plaque, Atherosclerotic* / metabolism
  • Signal Transduction

Substances

  • CD40 Antigens