CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice
Objective: Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand–receptor pair should reduce monocyte binding...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-02-01
|
| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877818306197 |
| id |
doaj-9aa1e09a965d493391f4ff36b42d349a |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Matthew Riopel Melanie Vassallo Erik Ehinger Jennifer Pattison Karen Bowden Holger Winkels Maria Wilson Ron de Jong Sanjay Patel Deepika Balakrishna James Bilakovics Andrea Fanjul Artur Plonowski Christopher J. Larson Klaus Ley Pedro Cabrales Joseph L. Witztum Jerrold M. Olefsky Yun Sok Lee |
| spellingShingle |
Matthew Riopel Melanie Vassallo Erik Ehinger Jennifer Pattison Karen Bowden Holger Winkels Maria Wilson Ron de Jong Sanjay Patel Deepika Balakrishna James Bilakovics Andrea Fanjul Artur Plonowski Christopher J. Larson Klaus Ley Pedro Cabrales Joseph L. Witztum Jerrold M. Olefsky Yun Sok Lee CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice Molecular Metabolism |
| author_facet |
Matthew Riopel Melanie Vassallo Erik Ehinger Jennifer Pattison Karen Bowden Holger Winkels Maria Wilson Ron de Jong Sanjay Patel Deepika Balakrishna James Bilakovics Andrea Fanjul Artur Plonowski Christopher J. Larson Klaus Ley Pedro Cabrales Joseph L. Witztum Jerrold M. Olefsky Yun Sok Lee |
| author_sort |
Matthew Riopel |
| title |
CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice |
| title_short |
CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice |
| title_full |
CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice |
| title_fullStr |
CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice |
| title_full_unstemmed |
CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice |
| title_sort |
cx3cl1-fc treatment prevents atherosclerosis in ldlr ko mice |
| publisher |
Elsevier |
| series |
Molecular Metabolism |
| issn |
2212-8778 |
| publishDate |
2019-02-01 |
| description |
Objective: Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand–receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis. We sought to reduce atherosclerosis by preventing monocyte-endothelial cell interactions through use of a long-acting CX3CR1 agonist. Methods: In this study, the chemokine domain of CX3CL1 was fused to the mouse Fc region to generate a long-acting soluble form of CX3CL1 suitable for chronic studies. CX3CL1-Fc or saline was injected twice a week (30 mg/kg) for 4 months into Ldlr knockout (KO) mice on an atherogenic western diet. Results: CX3CL1-Fc-treated Ldlr KO mice showed decreased en face aortic lesion surface area and reduced aortic root lesion size with decreased necrotic core area. Flow cytometry analyses of CX3CL1-Fc-treated aortic wall cell digests revealed a decrease in M1-like polarized macrophages and T cells. Moreover, CX3CL1-Fc administration reduced diet-induced atherosclerosis after switching from an atherogenic to a normal chow diet. In vitro monocyte adhesion studies revealed that CX3CL1-Fc treatment caused fewer monocytes to adhere to a human umbilical vein endothelial cell monolayer. Furthermore, a dorsal window chamber model demonstrated that CX3CL1-Fc treatment decreased in vivo leukocyte adhesion and rolling in live capillaries after short-term ischemia-reperfusion. Conclusion: These results indicate that CX3CL1-Fc can inhibit monocyte/endothelial cell adhesion as well as reduce atherosclerosis. Keywords: Fractalkine, CX3CR1, Atherosclerosis, Monocyte adhesion, Inflammation, Ldlr KO |
| url |
http://www.sciencedirect.com/science/article/pii/S2212877818306197 |
| work_keys_str_mv |
AT matthewriopel cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT melanievassallo cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT erikehinger cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT jenniferpattison cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT karenbowden cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT holgerwinkels cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT mariawilson cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT rondejong cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT sanjaypatel cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT deepikabalakrishna cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT jamesbilakovics cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT andreafanjul cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT arturplonowski cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT christopherjlarson cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT klausley cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT pedrocabrales cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT josephlwitztum cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT jerroldmolefsky cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice AT yunsoklee cx3cl1fctreatmentpreventsatherosclerosisinldlrkomice |
| _version_ |
1724896882829819904 |
| spelling |
doaj-9aa1e09a965d493391f4ff36b42d349a2020-11-25T02:15:23ZengElsevierMolecular Metabolism2212-87782019-02-012089101CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO miceMatthew Riopel0Melanie Vassallo1Erik Ehinger2Jennifer Pattison3Karen Bowden4Holger Winkels5Maria Wilson6Ron de Jong7Sanjay Patel8Deepika Balakrishna9James Bilakovics10Andrea Fanjul11Artur Plonowski12Christopher J. Larson13Klaus Ley14Pedro Cabrales15Joseph L. Witztum16Jerrold M. Olefsky17Yun Sok Lee18Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USADivision of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USADivision of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USADivision of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USADivision of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USADivision of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USACardiovascular and Metabolic Diseases Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, USADivision of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USADepartment of Bioengineering, University of California, San Diego, La Jolla, CA, USADivision of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USADivision of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Corresponding author. Stein Clinical Research Building, Room 227, 9500 Gilman Drive, La Jolla, CA, 92093, USA.Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Corresponding author. Stein Clinical Research Building, Room 231, 9500 Gilman Drive, MC# 0673, La Jolla, CA, 92093, USA.Objective: Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand–receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis. We sought to reduce atherosclerosis by preventing monocyte-endothelial cell interactions through use of a long-acting CX3CR1 agonist. Methods: In this study, the chemokine domain of CX3CL1 was fused to the mouse Fc region to generate a long-acting soluble form of CX3CL1 suitable for chronic studies. CX3CL1-Fc or saline was injected twice a week (30 mg/kg) for 4 months into Ldlr knockout (KO) mice on an atherogenic western diet. Results: CX3CL1-Fc-treated Ldlr KO mice showed decreased en face aortic lesion surface area and reduced aortic root lesion size with decreased necrotic core area. Flow cytometry analyses of CX3CL1-Fc-treated aortic wall cell digests revealed a decrease in M1-like polarized macrophages and T cells. Moreover, CX3CL1-Fc administration reduced diet-induced atherosclerosis after switching from an atherogenic to a normal chow diet. In vitro monocyte adhesion studies revealed that CX3CL1-Fc treatment caused fewer monocytes to adhere to a human umbilical vein endothelial cell monolayer. Furthermore, a dorsal window chamber model demonstrated that CX3CL1-Fc treatment decreased in vivo leukocyte adhesion and rolling in live capillaries after short-term ischemia-reperfusion. Conclusion: These results indicate that CX3CL1-Fc can inhibit monocyte/endothelial cell adhesion as well as reduce atherosclerosis. Keywords: Fractalkine, CX3CR1, Atherosclerosis, Monocyte adhesion, Inflammation, Ldlr KOhttp://www.sciencedirect.com/science/article/pii/S2212877818306197 |