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Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages
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Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in

Chaojun Tang1,2,3,4,5, Guona Chen1, Fan Wu1,6

  • 1Cyrus Tang Medical Institute, Soochow University, Rm 509, Bldg 703, 199 Ren'ai Road, Suzhou 215123, China.

Cardiovascular Research
|June 6, 2023
PubMed

Insights

Disturbed blood flow upregulates atypical chemokine receptor 5 (CCRL2), promoting atherosclerosis. This novel pathway involves chemerin and beta-2 integrin, offering new therapeutic targets for preventing plaque formation.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Molecular Medicine

Background:

  • Atherosclerosis is driven by leukocyte recruitment to arterial walls, particularly in areas of disturbed flow (d-flow).
  • Atypical chemokine receptors (ACKRs), including ACKR5 (CCRL2), are implicated in inflammatory processes.
  • CCRL2 is upregulated in endothelial cells under atherosclerotic conditions and d-flow.

Purpose of the Study:

  • To investigate the role of CCRL2 and its ligand chemerin in atherosclerosis.
  • To elucidate the underlying molecular mechanisms of CCRL2-mediated leukocyte recruitment in d-flow areas.

Main Methods:

  • Analysis of single-cell RNA sequencing data from mouse carotid arteries under d-flow.
  • Utilized CCRL2-/-ApoE-/- mice fed a high-fat diet to assess plaque formation.
  • Investigated chemerin's interaction with beta-2 integrin using biochemical assays and proximity ligation assays.

Main Results:

  • CCRL2 expression is increased in endothelial cells under d-flow and atherosclerotic conditions.
  • CCRL2 deficiency reduced atherosclerotic plaque formation in ApoE-/- mice, especially in d-flow regions.
  • Chemerin, via its protein disulfide isomerase-like activity, activates beta-2 integrin, enhancing monocyte adhesion and ERK1/2 phosphorylation.
  • Elevated serum chemerin levels were observed in patients with acute atherothrombotic stroke.

Conclusions:

  • Disturbed flow-induced CCRL2 promotes atherosclerotic plaque development through a novel CCRL2-chemerin-beta-2 integrin axis.
  • This pathway represents a potential therapeutic target for atherosclerosis prevention and treatment.
Abstract

Keywords:
AtherosclerosisCCRL2ChemerinMonocytePDI-like activity

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