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Human CD16+ monocytes promote a pro-atherosclerotic endothelial cell phenotype via CX3CR1-CX3CL1 interaction
Eva Roy-Chowdhury1, Nicolas Brauns1, Alexandra Helmke1
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
Insights
Human CD16+ monocytes, elevated in kidney failure, promote atherosclerosis by altering endothelial cell function. Their interaction with endothelial cells via CX3CR1-CX3CL1 signaling increases cardiovascular risk.
Area of Science:
- Immunology
- Cardiovascular Biology
- Renal Medicine
Background:
- Monocytes are key players in vascular inflammation and atherosclerosis.
- Non-classical CD16+ monocytes, expressing CX3CR1, are linked to cardiovascular events, especially in renal failure.
- The mechanisms driving this association in kidney disease remain unclear.
Purpose of the Study:
- To investigate how human CD16+ monocytes influence endothelial cell function.
- To elucidate the role of CD16+ monocytes in the heightened atherosclerosis risk observed in renal failure.
Main Methods:
- Co-incubation of CD16+ monocytes with human endothelium in vitro.
- Analysis of endothelial cell signaling pathways (STAT1, NF-κB).
- Measurement of gene and protein expression (CX3CL1, IL-1β, chemokines, adhesion molecules).
- Assessment of endothelial function (vasodilatation, stiffness, collagen production).
- In vivo studies using murine models of atherosclerosis with renal impairment.
Main Results:
- CD16+ monocytes significantly enhanced endothelial STAT1 and NF-κB phosphorylation.
- Upregulation of CX3CL1, IL-1β, chemokines, and adhesion molecules (ICAM1, VCAM1) by CD16+ monocytes.
- Decreased expression of endothelial nitric oxide synthase and increased collagen production.
- CX3CR1 on monocytes was crucial for increased endothelial stiffness in murine models.
- Monocyte-CX3CR1-CX3CL1 interaction mediated proatherosclerotic endothelial gene expression.
Conclusions:
- CD16+ monocytes directly induce proatherosclerotic changes in endothelial cells.
- The CX3CR1-CX3CL1 axis is a key mediator of CD16+ monocyte-driven endothelial dysfunction.
- These findings reveal a mechanism linking CD16+ monocytes to increased cardiovascular risk in renal failure.
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.
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