Decreased Atherosclerotic Lesion Formation in CX3CR1/Apolipoprotein E Double Knockout Mice
Abstract
Background Fractalkine (CX3CL1), a CX3C chemokine, is expressed in the vessel wall and mediates the firm adhesion and chemotaxis of leukocytes expressing its receptor, CX3CR1. A polymorphism in the CX3CR1 gene is associated with low CX3CR1 expression and reduced risk of acute coronary disease in humans. Methods and results We generated CX3CR1-deficient mice (CX3CR1(-/-)) by targeted gene disruption and crossed them with the proatherogenic apolipoprotein E-deficient mice (apoE(-/-)). Here we show that the extent of lipid-stained lesions in the thoracic aorta was reduced by 59% in CX3CR1/apoE double knockout mice compared with their CX3CR1(+/+)/apoE(-/-) littermates. The development of atherosclerosis in the aortic sinus was also markedly altered in the double knockout mice, with 50% reduction in macrophage accumulation. Although lesions of CX3CR1(-/-) mice were smaller in size, they retained a substantial accumulation of smooth muscle cells and collagen, features consistent with a stable plaque phenotype. Finally, CX3CR1(+/-)/apoE(-/-) mice showed the same reduction in atherosclerosis as the CX3CR1(-/-)/apoE(-/-) mice. Conclusions The CX3CR1-CX3CL1 pathway seems to play a direct and critical role in monocyte recruitment and atherosclerotic lesion development in a mouse model of human atherosclerosis.
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CX3CR1 and its ligand fractalkine have been implicated in recruitment of mononuclear phagocytes to sites of inflammation and injury and play roles in the pathogenesis of several inflammatory conditions including atherosclerosis, neuropathic pain, and asthma.
“CX3CR1 and its chemokine ligand fractalkine (CX3CL1) have been implicated in the recruitment of mononuclear phagocytes to sites of inflammation and injury (7, 10, 11) and play roles in the pathogenesis of several inflammatory conditions, including atherosclerosis (12, 13), neuropathic pain (14), and asthma (15).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [12]
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- Authors
- Combadière, C., Potteaux, S., Gao, J.-L., Esposito, B., Casanova, S., Lee, E. J., Debré, P., Tedgui, A., Murphy, P. M., & Mallat, Z.
- Affiliations
- From Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md (C.C., J.-L.G., P.M.M.); Institut National de la Santé et de la Recherche Médicale, INSERM U543, Laboratoire d’Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris, France (C.C., S.C., P.D.); INSERM U541, Institut Fédératif de Recherche “Circulation Paris VII,” Hôpital Lariboisière, Paris, France (S.P., B.E., A.T., Z.M.); and Laboratory of...
- National Institutes of Health (US)
- Venue
- Circulation
- Published
- 2003-02-25
- Volume
- 107
- Issue
- 7
- Pages
- 1009-1016
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2011363498
- Cited by
- 476
- References
- 2
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 11 · 2023: 10 · 2022: 6 · 2021: 11 · 2020: 13 · 2019: 13 · 2018: 12 · 2017: 16 · 2016: 15 · 2015: 24 · 2014: 31 · 2013: 25 · 2012: 36
- FWCI
- 10.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- CX3CR1, fractalkine, atherosclerosis, apolipoprotein E deficiency, double knockout mice, monocyte recruitment, macrophage accumulation, aortic plaque, chemokine signaling
- MeSH terms
- CX3C Chemokine Receptor 1, Alleles, Animals, Apolipoproteins E, Arteriosclerosis, Chemotaxis, Leukocyte, Membrane Proteins, Monocytes, Receptors, HIV, Receptors, Cytokine, Mice, Knockout, Gene Targeting, Receptors, Chemokine, Chemokines, CX3C, Mice, Chemokine CX3CL1
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