Human CD16+ monocytes promote a pro-atherosclerotic endothelial cell phenotype via CX3CR1-CX3CL1 interaction

Cardiovasc Res. 2021 May 25;117(6):1510-1522. doi: 10.1093/cvr/cvaa234.

Abstract

Aims: Monocytes are central for atherosclerotic vascular inflammation. The human non-classical, patrolling subtype, which expresses high levels of CD16 and fractalkine receptor CX3CR1, strongly associates with cardiovascular events. This is most marked in renal failure, a condition with excess atherosclerosis morbidity. The underlying mechanism is not understood. This study investigated how human CD16+ monocytes modulate endothelial cell function.

Methods and results: In patients with kidney failure, CD16+ monocyte counts were elevated and dynamically decreased within a year after transplantation, chiefly due to a drop in CD14+CD16+ cells. The CX3CR1 ligand CX3CL1 was similarly elevated in the circulation of humans and mice with renal impairment. CX3CL1 up-regulation was also observed close to macrophage rich human coronary artery plaques. To investigate a mechanistic basis of this association, CD16+CX3CR1HIGH monocytes were co-incubated with primary human endothelium in vitro. Compared to classical CD14+ monocytes or transwell cocultures, CD16+ monocytes enhanced endothelial STAT1 and NF-κB p65 phosphorylation, up-regulated expression of CX3CL1 and interleukin-1β, numerous CCL and CXCL chemokines and molecules promoting leucocyte patrolling and adhesion such as ICAM1 and VCAM1. Genes required for vasodilatation including endothelial nitric oxide synthase decreased while endothelial collagen production increased. Uraemic patients' monocytes enhanced endothelial CX3CL1 even more markedly. Their receptor CX3CR1 was required for enhanced aortic endothelial stiffness in murine atherosclerosis with renal impairment. CX3CR1 dose-dependently modulated monocyte-contact-dependent gene expression in human endothelium.

Conclusion: By demonstrating endothelial proatherosclerotic gene regulation in direct contact with CD16+ monocytes, in part via cellular CX3CR1-CX3CL1 interaction, our data delineate a mechanism how this celltype can increase cardiovascular risk.

Keywords: Chronic kidney disease; Endothelium; Monocytes; Atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • CX3C Chemokine Receptor 1 / genetics
  • CX3C Chemokine Receptor 1 / metabolism*
  • Cell Communication
  • Cells, Cultured
  • Chemokine CX3CL1 / genetics
  • Chemokine CX3CL1 / metabolism*
  • Coculture Techniques
  • Disease Models, Animal
  • GPI-Linked Proteins / metabolism
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Kidney Diseases / immunology
  • Kidney Diseases / metabolism
  • Kidney Diseases / therapy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Phenotype
  • Plaque, Atherosclerotic*
  • Receptors, IgG / metabolism*
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Signal Transduction
  • Uremia / immunology
  • Uremia / metabolism

Substances

  • CX3C Chemokine Receptor 1
  • CX3CL1 protein, human
  • CX3CR1 protein, human
  • Chemokine CX3CL1
  • Cx3cl1 protein, mouse
  • Cx3cr1 protein, mouse
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Receptors, IgG
  • Receptors, LDL