Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis

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Title: Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis
Authors: Bruen, Robyn
Curley, Sean
Kajani, Sarina
Crean, Daniel
O’Reilly, Marcella E.
Lucitt, Margaret B.
Godson, Catherine
McGillicuddy, Fiona C.
Belton, Orina
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Date: 6-Nov-2017
Online since: 2019-04-08T11:24:00Z
Abstract: Background: Macrophages play a pivotal role in atherosclerotic plaque development. Recent evidence has suggested the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can attenuate pro-inflammatory responses in macrophages. We hypothesized that liraglutide could limit atherosclerosis progression in vivo via modulation of the inflammatory response. Methods: Human THP-1 macrophages and bone marrow-derived macrophages, from both wild-type C57BL/6 (WT) and apolipoprotein E null mice (ApoE−/−) were used to investigate the effect of liraglutide on the inflammatory response in vitro. In parallel, ApoE−/− mice were fed a high-fat (60% calories from fat) high-cholesterol (1%) diet for 8 weeks to induce atherosclerotic disease progression with/without daily 300 μg/kg liraglutide administration for the final 6 weeks. Macrophages were analysed for MΦ1 and MΦ2 macrophage markers by Western blotting, RT-qPCR, ELISA and flow cytometry. Atherosclerotic lesions in aortae from ApoE−/− mice were analysed by en face staining and monocyte and macrophage populations from bone marrow derived cells analysed by flow cytometry. Results: Liraglutide decreased atherosclerotic lesion formation in ApoE−/− mice coincident with a reduction in pro-inflammatory and increased anti-inflammatory monocyte/macrophage populations in vivo. Liraglutide decreased IL-1beta in MΦ0 THP-1 macrophages and bone marrow-derived macrophages from WT mice and induced a significant increase in the MΦ2 surface marker mannose receptor in both MΦ0 and MΦ2 macrophages. Significant reduction in total lesion development was found with once daily 300 μg/kg liraglutide treatment in ApoE−/− mice. Interestingly, liraglutide inhibited disease progression at the iliac bifurcation suggesting that it retards the initiation and development of disease. These results corresponded to attenuated MΦ1 markers (CCR7, IL-6 and TNF-alpha), augmented MΦ2 cell markers (Arg-1, IL-10 and CD163) and finally decreased MΦ1-like monocytes and macrophages from bone marrow-derived cells. Conclusions: This data supports a therapeutic role for liraglutide as an atheroprotective agent via modulating macrophage cell fate towards MΦ2 pro-resolving macrophages.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: BMC
Journal: Cardiovascular Diabetology
Volume: 16
Issue: 143
Start page: 1
End page: 13
Copyright (published version): 2017 the Authors
Keywords: MΦ2 macrophagesMonocytesAnti-inflammatoryPlaque microenvironmentAtherosclerosis
DOI: 10.1186/s12933-017-0626-3
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Medicine Research Collection
Veterinary Medicine Research Collection

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