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Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages
Published on: August 12, 2019
Fractalkine promotes human monocyte survival via a reduction in oxidative stress
Gemma E White1, Eileen McNeill1, Keith M Channon1
1From the Sir William Dunn School of Pathology (G.E.W., D.R.G.), Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital (E.M., K.M.C.), and Wellcome Trust Centre for Human Genetics (E.M., K.M.C.), University of Oxford, Oxford, United Kingdom.
Insights
Fractalkine (CX3CL1) significantly enhances human monocyte survival by reducing oxidative stress, suggesting a key role in preventing atherosclerosis and offering a potential therapeutic target for cardiovascular disease.
Area of Science:
- Immunology
- Cardiovascular Biology
- Cell Biology
Background:
- Fractalkine (CX3CL1) and its receptor CX3CR1 are implicated in atherogenesis.
- CX3CR1 is present on various cells involved in atherosclerosis, with a notable role in monocyte function.
Purpose of the Study:
- To investigate the role of CX3CL1 in human monocyte survival.
- To elucidate the mechanism by which CX3CL1 inhibits monocyte apoptosis.
Main Methods:
- Human monocytes were serum-starved to induce apoptosis.
- The effects of CX3CL1 on monocyte survival and intracellular reactive oxygen species (ROS) were assessed.
- Antioxidants were used to investigate the role of oxidative stress.
Main Results:
- CX3CL1 demonstrated a dose-dependent, potent antiapoptotic effect on human monocytes, particularly nonclassical monocytes.
- The prosurvival effect was more pronounced with full-length CX3CL1 compared to the chemokine-domain only.
- CX3CL1 reduced intracellular ROS levels, and inhibiting oxidative stress prevented monocyte apoptosis.
Conclusions:
- CX3CL1 exerts a significant antiapoptotic effect on human monocytes by reducing oxidative stress.
- These findings highlight CX3CL1's crucial role in human atherogenesis.
- CX3CL1 represents a potential novel therapeutic target for cardiovascular disease.
Objective:
The CX3C chemokine fractalkine (CX3CL1) has a critical role in the development of atherogenesis because apolipoprotein-E-deficient mice lacking CX3CL1 or its receptor CX3CR1 develop smaller plaques and polymorphisms in CX3CR1 are associated with altered risk of cardiovascular disease. CX3CR1 is found on numerous cell types involved in atherogenesis but seems to have a key role in monocyte function. We aimed to elucidate the role of CX3CL1 in human monocyte survival and determine the mechanism by which CX3CL1 spares monocytes from apoptosis.
Approach And Results:
Primary human monocytes were prepared from healthy donors and subjected to serum-starvation to induce spontaneous apoptosis. The addition of CX3CL1, but not other chemokines tested, promoted monocyte survival in a dose-dependent manner with full-length CX3CL1 (including the mucin stalk) having a more potent antiapoptotic effect than chemokine-domain CX3CL1. The prosurvival effect of CX3CL1 was evident in both monocyte subsets although nonclassical monocytes were more prone to spontaneous apoptosis. In addition, we found that the effect of CX3CL1 was independent of CX3CR1 genotype. Serum-starvation increased the level of intracellular reactive oxygen species, and this was reduced by the addition of CX3CL1. Inhibition of oxidative stress with an antioxidant prevented monocyte apoptosis, indicating that this is the dominant mechanism of cell death targeted by CX3CL1.
Conclusions:
CX3CL1 has a substantial and highly reproducible antiapoptotic effect on human monocytes, via a mechanism involving a reduction in oxidative stress. This suggests that CX3CL1 is likely to play a key role in human atherogenesis and may provide a novel therapeutic target in cardiovascular disease.
