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

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.