Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent ß2 integrin activation in monocytes.
Cardiovasc Res
; 119(9): 1811-1824, 2023 08 07.
Article
en En
| MEDLINE
| ID: mdl-37279540
ABSTRACT
AIMS:
Chemoattractants and their cognate receptors are essential for leucocyte recruitment during atherogenesis, and atherosclerotic plaques preferentially occur at predilection sites of the arterial wall with disturbed flow (d-flow). In profiling the endothelial expression of atypical chemoattractant receptors (ACKRs), we found that Ackr5 (CCRL2) was up-regulated in an endothelial subpopulation by atherosclerotic stimulation. We therefore investigated the role of CCRL2 and its ligand chemerin in atherosclerosis and the underlying mechanism. METHODS ANDRESULTS:
By analysing scRNA-seq data of the left carotid artery under d-flow and scRNA-seq datasets GSE131776 of ApoE-/- mice from the Gene Expression Omnibus database, we found that CCRL2 was up-regulated in one subpopulation of endothelial cells in response to d-flow stimulation and atherosclerosis. Using CCRL2-/-ApoE-/- mice, we showed that CCRL2 deficiency protected against plaque formation primarily in the d-flow areas of the aortic arch in ApoE-/- mice fed high-fat diet. Disturbed flow induced the expression of vascular endothelial CCRL2, recruiting chemerin, which caused leucocyte adhesion to the endothelium. Surprisingly, instead of binding to monocytic CMKLR1, chemerin was found to activate ß2 integrin, enhancing ERK1/2 phosphorylation and monocyte adhesion. Moreover, chemerin was found to have protein disulfide isomerase-like enzymatic activity, which was responsible for the interaction of chemerin with ß2 integrin, as identified by a Di-E-GSSG assay and a proximity ligation assay. For clinical relevance, relatively high serum levels of chemerin were found in patients with acute atherothrombotic stroke compared to healthy individuals.CONCLUSIONS:
Our findings indicate that d-flow-induced CCRL2 promotes atherosclerotic plaque formation via a novel CCRL2-chemerin-ß2 integrin axis, providing potential targets for the prevention or therapeutic intervention of atherosclerosis.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Antígenos CD18
/
Aterosclerosis
/
Placa Aterosclerótica
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Cardiovasc Res
Año:
2023
Tipo del documento:
Article
País de afiliación:
China