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

J. Lauran Stöger; Marieke C. S. Boshuizen; Gemma Brufau; Marion J. J. Gijbels; Ine M. J. Wolfs; Saskia van der Velden; Chantal C. H. Pöttgens; Monique N. Vergouwe; Erwin Wijnands; Linda Beckers; Pieter Goossens; Anja Kerksiek; Rick Havinga; Werner Müller; Dieter Lütjohann; Albert K. Groen; Menno P. J. de Winther

doi:10.1160/TH16-01-0043

Thrombosis and Haemostasis, Table of Contents

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^*

¹Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

²Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands

,

Marieke C. S. Boshuizen^*

¹Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Gemma Brufau

³Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

,

Marion J. J. Gijbels

¹Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

²Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands

⁴Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands

,

Ine M. J. Wolfs

⁴Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands

,

Saskia van der Velden

¹Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Chantal C. H. Pöttgens

²Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands

,

Monique N. Vergouwe

²Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands

,

Erwin Wijnands

⁴Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands

,

Linda Beckers

¹Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Pieter Goossens

²Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands

⁵Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, Marseille, France

,

Anja Kerksiek

⁶Institute for Clinical Chemistry and Clinical Pharmacology, Medical University Clinics Bonn, Bonn, Germany

,

Rick Havinga

³Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

,

Werner Müller

⁷Faculty of Life Sciences, University of Manchester, Manchester, UK

,

Dieter Lütjohann

⁶Institute for Clinical Chemistry and Clinical Pharmacology, Medical University Clinics Bonn, Bonn, Germany

,

Albert K. Groen

³Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

⁸Amsterdam Diabetes Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Menno P. J. de Winther

¹Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

› Author Affiliations

Abstract

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

Full Text

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