Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium.

Gencer, Selin; Döring, Yvonne; Jansen, Yvonne; Bayasgalan, Soyolmaa; Yan, Yi; Bianchini, Mariaelvy; Cimen, Ismail; Müller, Madeleine; Peters, Linsey J F; Megens, Remco T A; von Hundelshausen, Philipp; Duchene, Johan; Lemnitzer, Patricia; Soehnlein, Oliver; Weber, Christian; van der Vorst, Emiel P C (2022). Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium. Basic research in cardiology, 117(1), p. 30. Springer 10.1007/s00395-022-00937-4

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Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12-CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe-/- mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3's role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways.

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