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. 2025 Dec:411:120517.
doi: 10.1016/j.atherosclerosis.2025.120517. Epub 2025 Nov 17.

Endothelial CD40L serves as a pro-atherogenic adhesion receptor in the inflamed vasculature

Philipp Scherrer  1 , Timoteo Marchini  2 , Xiaowei Li  2 , Abed Al Hadi El Rabih  2 , Jan Pennig  2 , Lucia Sol Mitre  3 , Juana Dominguez  2 , Mark Colin Gissler  2 , Guido Pisani  2 , Nathaly Anto Michel  4 , Timothy Mwinyella  2 , Tijani Abogunloko  3 , Natalie Hoppe  2 , Lisa Spiga  2 , Daniela Stallmann  2 , Hauke Horstmann  5 , Patrick Malcolm Siegel  2 , Sophie Hansen  2 , Ingo Hilgendorf  2 , Esther Lutgens  6 , Christian Weber  7 , Norbert Gerdes  8 , Andreas Zirlik  4 , Dirk Westermann  2 , Florian Willecke  9 , Dennis Wolf  10
Affiliations
Free article

Endothelial CD40L serves as a pro-atherogenic adhesion receptor in the inflamed vasculature

Philipp Scherrer et al. Atherosclerosis. 2025 Dec.
Free article

Abstract

Background and aims: The repertoire of adhesion receptors and ligands is supported by molecules, which are primarily recognized for their roles in immunity. We have recently shown that the co-stimulatory molecule CD40 ligand (CD154/CD40L) is pro-atherogenic and serves as an adhesive ligand for cells expressing the integrin Mac-1 (CD11b/CD18). Here, we studied the role of endothelial CD40L in several models of cardiovascular inflammation.

Methods and results: We generated mice with an endothelial cell-specific deficiency of CD40L, Bmx-CreERT2+Cd40lgfl/flApoe-/- (EC-CD40L-KO), and Cd40lgfl/flApoe-/- as controls. In a model of atherosclerosis, EC-CD40L-KO mice developed on average 39.4 ± 14.7 % smaller atherosclerotic plaques after 10 weeks of the conditional genetic deficiency compared to controls. Plaques from EC-CD40L-KO mice contained less macrophages, lipids and more collagen. In intravital microscopy of inflamed mesenteric venules, leukocyte adhesion was reduced 3.1-fold in EC-CD40L-KO mice with a similar effect on slow rolling. In a model of thioglycolate-induced peritonitis, leukocyte migration into the peritoneal cavity was reduced by 38.2 ± 16.2 % in EC-CD40L-KO mice compared to controls after 72 h. Furthermore, 7 days after a permanent surgical ligation of the Left Anterior Descending (LAD) coronary artery, significantly fewer Mac-1-expressing neutrophils and macrophages were detected in the infarcted myocardium in the absence of endothelial CD40L.

Conclusions: In this functional validation study, we demonstrate that endothelial cell-expressed CD40L serves as an adhesion molecule in different models of acute inflammation in the aortic, peritoneal, mesenteric, and coronary vasculature. CD40L may therefore represent a promising therapeutic target at the interface of adaptive immunity and myeloid inflammation.

Keywords: Atherosclerosis; CD40L; Inflammation; Leukocyte migration; Myocardial infarction.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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