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Published on: October 17, 2017
CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival
Limor Landsman1, Liat Bar-On, Alma Zernecke
1Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Insights
The CX3C chemokine axis, involving CX3CR1 and its ligand CX3CL1, is crucial for monocyte survival. This interaction prevents monocyte and foam cell death, impacting atherosclerosis development.
Area of Science:
- Immunology
- Cardiovascular Research
- Molecular Biology
Background:
- CX3CR1 is a chemokine receptor with a single ligand, CX3CL1 (fractalkine).
- Monocytes express CX3CR1, with higher levels on CD16(+) (human) and Gr1(low) (murine) subsets.
- CX3CR1 gene polymorphisms are linked to atherosclerosis risk.
Purpose of the Study:
- To elucidate the mechanistic role of the CX3C chemokine axis in monocyte survival and atherogenesis.
- To investigate the impact of CX3CR1 deficiency on monocyte levels and atherosclerosis development.
- To determine if CX3CL1-CX3CR1 interactions provide essential survival signals for monocytes and foam cells.
Main Methods:
- Studied mice deficient in CX3CR1 or CX3CL1 under steady-state and inflammatory conditions.
- Utilized Bcl2 transgene to assess the role of survival signals.
- Examined the effect of enforced monocyte and foam cell survival on atherogenesis in CX3CR1-deficient mice.
- Investigated the rescue of cultured human monocytes from cell death by CX3CL1.
Main Results:
- Absence of CX3CR1 or CX3CL1 significantly reduced Gr1(low) blood monocyte levels.
- Introduction of a Bcl2 transgene restored wild-type monocyte levels, indicating a survival role for the CX3C axis.
- CX3CL1 rescued cultured human monocytes from induced cell death.
- Enforced survival of monocytes and foam cells restored atherogenesis in CX3CR1-deficient mice.
Conclusions:
- The CX3CL1-CX3CR1 interaction provides a critical survival signal for monocytes and plaque-resident phagocytes.
- Increased death of monocytes and foam cells due to the absence of this signal may explain the CX3C family's role in atherogenesis.
- Targeting the CX3C chemokine pathway could offer therapeutic strategies for atherosclerosis.
Abstract:
CX(3)CR1 is a chemokine receptor with a single ligand, the membrane-tethered chemokine CX(3)CL1 (fractalkine). All blood monocytes express CX(3)CR1, but its levels differ between the main 2 subsets, with human CD16(+) and murine Gr1(low) monocytes being CX(3)CR1(hi). Here, we report that absence of either CX(3)CR1 or CX(3)CL1 results in a significant reduction of Gr1(low) blood monocyte levels under both steady-state and inflammatory conditions. Introduction of a Bcl2 transgene restored the wild-type phenotype, suggesting that the CX(3)C axis provides an essential survival signal. Supporting this notion, we show that CX(3)CL1 specifically rescues cultured human monocytes from induced cell death. Human CX(3)CR1 gene polymorphisms are risk factors for atherosclerosis and mice deficient for the CX(3)C receptor or ligand are relatively protected from atherosclerosis development. However, the mechanistic role of CX(3)CR1 in atherogenesis remains unclear. Here, we show that enforced survival of monocytes and plaque-resident phagocytes, including foam cells, restored atherogenesis in CX(3)CR1-deficent mice. The fact that CX(3)CL1-CX(3)CR1 interactions confer an essential survival signal, whose absence leads to increased death of monocytes and/or foam cells, might provide a mechanistic explanation for the role of the CX(3)C chemokine family in atherogenesis.
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