title: Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes.
abstract: 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.
authors.forename: J Lauran
authors.initials: JL
authors.lastname: Stöger
authors.forename: Marieke C S
authors.initials: MC
authors.lastname: Boshuizen
authors.forename: Gemma
authors.initials: G
authors.lastname: Brufau
authors.forename: Marion J J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Ine M J
authors.initials: IM
authors.lastname: Wolfs
authors.forename: Saskia
authors.initials: S
authors.lastname: van der Velden
authors.forename: Chantal C H
authors.initials: CC
authors.lastname: Pöttgens
authors.forename: Monique N
authors.initials: MN
authors.lastname: Vergouwe
authors.forename: Erwin
authors.initials: E
authors.lastname: Wijnands
authors.forename: Linda
authors.initials: L
authors.lastname: Beckers
authors.forename: Pieter
authors.initials: P
authors.lastname: Goossens
authors.forename: Anja
authors.initials: A
authors.lastname: Kerksiek
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Prof. M. P. J. de Winther, PhD, Experimental Vascular Biology, Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands, Tel.: +31 20 5666762, E-mail: m.dewinther@amc.uva.nl.
authors.forename: Menno P J
authors.initials: MP
authors.lastname: de Winther
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D001693:Biological Transport, Active; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D006937:Hypercholesterolemia / Q000517:prevention & control; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D053701:Receptors, Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
chemical_list: D002784:Cholesterol; D002791:Cholesterol, Dietary; D053701:Receptors, Interleukin-10; D011973:Receptors, LDL; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2
keywords: Interleukin-10; TICE; atherosclerosis; cholesterol; myeloid cells