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Thromb Haemost 2016; 116(03): 565-577
DOI: 10.1160/TH16-01-0043
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes

J. Lauran Stöger   *
1   Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
,
Marieke C. S. Boshuizen   *
1   Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Gemma Brufau
3   Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Marion J. J. Gijbels
1   Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
4   Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands
,
Ine M. J. Wolfs
4   Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands
,
Saskia van der Velden
1   Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Chantal C. H. Pöttgens
2   Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
,
Monique N. Vergouwe
2   Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
,
Erwin Wijnands
4   Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands
,
Linda Beckers
1   Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Pieter Goossens
2   Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
5   Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, Marseille, France
,
Anja Kerksiek
6   Institute for Clinical Chemistry and Clinical Pharmacology, Medical University Clinics Bonn, Bonn, Germany
,
Rick Havinga
3   Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Werner Müller
7   Faculty of Life Sciences, University of Manchester, Manchester, UK
,
Dieter Lütjohann
6   Institute for Clinical Chemistry and Clinical Pharmacology, Medical University Clinics Bonn, Bonn, Germany
,
Albert K. Groen
3   Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
8   Amsterdam Diabetes Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Menno P. J. de Winther
1   Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations Financial support: Menno P. J. de Winther is an established investigator of the Netherlands Heart Foundation (2007T067). He is supported by the Netherlands Heart Foundation (#2010B022 and CVON 2011/ B019: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS]), NWO (#TOP91208001), the Netherlands CardioVascular Research Initiative (CVON2011–19) and holds an AMC fellowship.
Further Information

Publication History

Received: 18 January 2016

Accepted after major revision: 25 May 2016

Publication Date:
29 November 2017 (online)

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Summary

Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower myeloid cell accumulation and more apoptosis in the lesions. Additionally, a profound reduction in plasma and liver cholesterol was observed upon myeloid IL-10R1 deficiency, which was reflected in plaque lipid content. This decreased hypercholesterolaemia was associated with lowered very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, likely as a response to decreased intestinal cholesterol absorption. In addition, IL-10R1 deficient mice demonstrated substantially higher faecal sterol loss caused by increased non-biliary cholesterol efflux. The induction of this process was linked to impaired ACAT2-mediated esterification of liver and plasma cholesterol. Overall, myeloid cells do not contribute to IL-10-mediated atheroprotection. In addition, this study demonstrates a novel connection between IL-10-mediated inflammation and cholesterol homeostasis in atherosclerosis. These findings make us reconsider IL-10 as a beneficial influence on atherosclerosis.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Interleukin-10 - myeloid cells - atherosclerosis - cholesterol - TICE

* These authors contributed equally.


 

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