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

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: https://doi.org/10.1160/TH16-01-0043
Issue: 2016: 116/3 (Sep) pp. 403–585
Pages: 565-577
Ahead of Print: 2016-06-30

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

Online Supplementary Material

See also Mach, Brandt

J. L. Stöger (1, 2), M. C. S. Boshuizen (1), G. Brufau (3), M. J. J. Gijbels (1, 2, 4), I. M. J. Wolfs (4), S. van der Velden (1), C. C. H. Pöttgens (2), M. N. Vergouwe (2), E. Wijnands (4), L. Beckers (1), P. Goossens (2, 5), A. Kerksiek (6), R. Havinga (3), W. Müller (7), D. Lütjohann (6), A. K. Groen (3, 8), M. P. J. de Winther (1)

(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; (3) Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; (4) Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands; (5) Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, Marseille, France; (6) Institute for Clinical Chemistry and Clinical Pharmacology, Medical University Clinics Bonn, Bonn, Germany; (7) Faculty of Life Sciences, University of Manchester, Manchester, UK; (8) Amsterdam Diabetes Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Keywords

Atherosclerosis, cholesterol, interleukin-10, myeloid cells, TICE

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.

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