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SHR Neuro Cancer Cardio Lipid Metab Microb

Scherrer, P; Marchini, T; Li, X; El, Rabih, AAH; Pennig, J; Mitre, LS; Dominguez, J; Gissler, MC; Pisani, G; Michel, NA; Mwinyella, T; Abogunloko, T; Hoppe, N; Spiga, L; Stallmann, D; Horstmann, H; Siegel, PM; Hansen, S; Hilgendorf, I; Lutgens, E; Weber, C; Gerdes, N; Zirlik, A; Westermann, D; Willecke, F; Wolf, D.
Endothelial CD40L serves as a pro-atherogenic adhesion receptor in the inflamed vasculature.
Atherosclerosis. 2025; 411:120517 Doi: 10.1016/j.atherosclerosis.2025.120517
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Co-authors Med Uni Graz

Anto Michel Nathaly

Zirlik Andreas

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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-Cre^ERT2+Cd40lg^fl/flApoe^-/- (EC-CD40L-KO), and Cd40lg^fl/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.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Atherosclerosis - metabolism, pathology, genetics

CD40 Ligand - genetics, metabolism, deficiency

Mice, Knockout - administration & dosage

Peritonitis - metabolism, pathology, genetics, chemically induced

Disease Models, Animal - administration & dosage

Cell Adhesion - administration & dosage

Endothelial Cells - metabolism, pathology

Plaque, Atherosclerotic - administration & dosage

Leukocyte Rolling - administration & dosage

Mice, Inbred C57BL - administration & dosage

Inflammation - metabolism, pathology

Leukocytes - metabolism

Mice - administration & dosage

Male - administration & dosage

Macrophage-1 Antigen - metabolism

Platelet Glycoprotein GPIb-IX Complex - administration & dosage

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