Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Endothelial CD40L serves as pro-inflammatory leukocyte adhesion receptor in early atherosclerosis
P. Scherrer1, X. Li1, M. C. Gissler1, J. Pennig1, N. Anto Michel2, I. Hilgendorf1, P. Stachon1, N. Gerdes3, A. Zirlik2, F. Willecke4, D. Wolf1
1Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH, Freiburg im Breisgau; 2Klinische Abteilung für Kardiologie, LKH-Univ. Klinikum Graz - Universitätsklinik für Innere Medizin, Graz, AT; 3Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Düsseldorf; 4Allgemeine und Interventionelle Kardiologie/Angiologie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen;
Introduction: Whole body genetic deficiency of the co-stimulatory molecule CD40 ligand (CD154/CD40L) prevents atherosclerosis in mice. We have previously demonstrated that CD40L serves as ligand for the myeloid cell expressed integrin Mac-1 (CD11b/CD18). Here we used a genetic deficiency of CD40L in endothelial cells to interrogate the role of endothelial cell-expressed CD40L as novel adhesion receptor in atherosclerosis and acute inflammation.

Methods & Results: To induce endothelial cell deficiency of CD40L we injected tamoxifen in 8-week-old male CD40Lfl/fl BMX-Cre+ ApoE-/- (EC-CD40L-KO) or CD40Lfl/fl BMX-Cre-  ApoE-/- (control) mice. Atherosclerotic lesion burden was assessed after an additional 10 and 20 weeks on a chow diet. After 18 weeks EC-CD40L-KO mice had smaller atherosclerotic plaques in the aorta compared with control mice (lesion-size/total wall area: 31.40±3.2% vs. 44.93±2.2%), while 28-week-old mice showed no difference in lesion size. Atherosclerotic lesions of 18-week-old EC-CD40L-KO mice contained less macrophages and lipids and more collagen than the control group. We did not detect changes in the plaque composition in 28-week-old mice. In intravital microscopy, adhering leukocytes were significantly reduced in mesenteric venules of 6-week-old EC-CD40L-KO compared with control mice (1.78 ± 0.28 vs. 4.57 ± 0.60). In addition, in a model of thioglycolate induced sterile peritonitis, we found significantly less cells in the peritoneal cavity after 72h in EC-CD40L-KO mice vs. control mice (12.1*106 ± 1.9*106 vs. 19.5*106± 2.7*106). These findings suggest that endothelial CD40L serves as adhesion factor in inflammation.         
                                                                                                                     
Conclusion: Endothelial CD40L-deficiency leads to decreased plaque size and a more stable plaque composition in early atherosclerosis (18 weeks), but not in advanced atherosclerosis (28 weeks). These findings demonstrate that the recruitment of leukocytes into developing atherosclerotic plaques is critical in early atherosclerosis, but not in the later stages of disease when alternative mechanisms, such as in situ proliferation, overwhelm.

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