2. Academic Validation
  3. Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in monocytes

Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in monocytes

  • Cardiovasc Res. 2023 Jun 4;cvad085. doi: 10.1093/cvr/cvad085.
Chaojun Tang 1 2 3 4 5,  Guona Chen 1,  Fan Wu 1 6,  Yiren Cao 1,  Fei Yang 1,  Tao You 1 7,  Chu Liu 1,  Menglu Li 1,  Shuhong Hu 1,  Lijie Ren 1 3,  Qiongyu Lu 1 3,  Wei Deng 1,  Ying Xu 3 6,  Guixue Wang 5 8,  Hanjoong Jo 9,  Yonghong Zhang 10 11,  Yi Wu 1 2 3 11 4,  Brian A Zabel 12,  Li Zhu 1 2 3 11 13 4 5
Affiliations

Affiliations

  • 1 Cyrus Tang Medical Institute.
  • 2 Collaborative Innovation Center of Hematology of Jiangsu Province.
  • 3 Suzhou Key Laboratory of Thrombosis and Vascular Biology.
  • 4 National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China.
  • 5 JinFeng Laboratory, Chongqing, China.
  • 6 Cambridge-Suda Genomic Resource Center.
  • 7 Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China.
  • 8 Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China.
  • 9 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • 10 Department of Epidemiology School of Public Health.
  • 11 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases.
  • 12 Palo Alto Veterans Institute for Research (PAVIR), Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, CA, USA.
  • 13 The Ninth Affiliated Hospital, Soochow University, Suzhou, China.
PMID: 37279540 DOI: 10.1093/cvr/cvad085
Abstract

Aims: Chemoattractants and their cognate receptors are essential for leukocyte 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 upregulated 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 and results: By analyzing scRNA-seq data of the left carotid artery (LCA) under d-flow and scRNA-seq datasets GSE131776 of ApoE-/- mice from the Gene Expression Omnibus database, we found that CCRL2 was upregulated 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 (HFD). Disturbed flow induced the expression of vascular endothelial CCRL2, recruiting chemerin, which caused leukocyte adhesion to the endothelium. Surprisingly, instead of binding to monocytic CMKLR1, chemerin was found to activate β2 Integrin, enhancing ERK1/2 phosphorylation and monocyte adhesion. Moreover, chemerin was found to have protein disulfide isomerase (PDI)-like enzymatic activity, which was responsible for the interaction of chemerin with β2 Integrin, as identified by a Di-E-GSSG assay and a proximity ligation assay (PLA). For clinical relevance, relatively high serum levels of chemerin were found in patients with acute atherothrombotic stroke (AAS) compared to healthy individuals.

Conclusions: Our findings indicate that d-flow-induced CCRL2 promotes atherosclerotic plaque formation via a novel CCRL2-chemerin-β2 Integrin axis, providing potential targets for the prevention or therapeutic intervention of atherosclerosis.

Keywords

Atherosclerosis; CCRL2; Chemerin; Monocyte; PDI-like activity.

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