@article{aa18418949b249aea1104c7fd34b72c9,
title = "CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice",
abstract = "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 = "Atherosclerosis, CX3CR1, Fractalkine, Inflammation, Ldlr KO, Monocyte adhesion",
author = "Matthew Riopel and Melanie Vassallo and Erik Ehinger and Jennifer Pattison and Karen Bowden and Holger Winkels and Maria Wilson and {de Jong}, Ron and Sanjay Patel and Deepika Balakrishna and James Bilakovics and Andrea Fanjul and Artur Plonowski and Larson, {Christopher J.} and Klaus Ley and Pedro Cabrales and Witztum, {Joseph L.} and Olefsky, {Jerrold M.} and Lee, {Yun Sok}",
note = "Funding Information: This research was supported from grants awarded by the US National Institute of Diabetes and Digestive and Kidney Diseases ( DK074868 , DK063491 , and DK101395 ), National Heart, Lung, and Blood Institute ( HL088093 awarded to J.L.W.) and a UCSD/UCLA Diabetes Research Center P&F grant . MR is supported by a postdoctoral fellowship from the American Heart Association ( 16POST29990015 ). This work was also supported by a grant from Takeda California, Inc . Funding Information: This research was supported from grants awarded by the US National Institute of Diabetes and Digestive and Kidney Diseases (DK074868, DK063491, and DK101395), National Heart, Lung, and Blood Institute (HL088093 awarded to J.L.W.) and a UCSD/UCLA Diabetes Research Center P&F grant. MR is supported by a postdoctoral fellowship from the American Heart Association (16POST29990015). This work was also supported by a grant from Takeda California, Inc. Funding Information: RDJ, SP, DB, JB, and, AF are employed by Takeda California, Inc. MW was employed by Takeda California Inc., but is now employed by Genentech. AP was employed by Takeda California Inc., but is now employed by Seal Rock Therapeutics, Inc. RDJ was employed by Takeda California Inc., but is now the principal at Ron de Jong Consulting, LLC. YSL and JMO have received past research funding from Takeda California Inc. JLW is a consultant for Ionis Pharmaceuticals and has patents covering the commercial use of oxidation-specific epitopes held by the University of California. CX3CL1/CX3CR1 and related methods of use reported in this study are covered in patent 9764001 by J.M.O and Y.S.L. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2019",
month = feb,
doi = "10.1016/j.molmet.2018.11.011",
language = "English (US)",
volume = "20",
pages = "89--101",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
}