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

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.

[1]  H. Sokol,et al.  Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production. , 2015, Cell metabolism.

[2]  P. Aukrust,et al.  Interleukin-10 increases reverse cholesterol transport in macrophages through its bidirectional interaction with liver X receptor α. , 2014, Biochemical and biophysical research communications.

[3]  C. Klein,et al.  Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. , 2014, Immunity.

[4]  G. Friedlander,et al.  Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. , 2014, Immunity.

[5]  B. Pillot,et al.  Transintestinal Cholesterol Excretion Is an Active Metabolic Process Modulated by PCSK9 and Statin Involving ABCB1 , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[6]  L. Havekes,et al.  Interactions between inflammation and lipid metabolism: relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis. , 2013, Atherosclerosis.

[7]  T. V. van Berkel,et al.  Trans-intestinal cholesterol efflux is not mediated through high density lipoprotein , 2012, Journal of Lipid Research.

[8]  L. Goedeke,et al.  Regulation of cholesterol homeostasis , 2012, Cellular and Molecular Life Sciences.

[9]  C. Klein,et al.  IL‐10 and IL‐10 receptor defects in humans , 2011, Annals of the New York Academy of Sciences.

[10]  Yuguang Lin,et al.  A Reappraisal of the Mechanism by Which Plant Sterols Promote Neutral Sterol Loss in Mice , 2011, PloS one.

[11]  J. Mehta,et al.  AAV/hSTAT3-gene delivery lowers aortic inflammatory cell infiltration in LDLR KO mice on high cholesterol. , 2010, Atherosclerosis.

[12]  R. Webb,et al.  Interleukin-10 inhibits the in vivo and in vitro adverse effects of TNF-alpha on the endothelium of murine aorta. , 2010, American journal of physiology. Heart and circulatory physiology.

[13]  Hong-wei Wang,et al.  Interleukin‐10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  A. Groen,et al.  Transintestinal cholesterol efflux. , 2010, Current opinion in lipidology.

[15]  L. Groebe,et al.  Monocytes/macrophages and/or neutrophils are the target of IL‐10 in the LPS endotoxemia model , 2010, European journal of immunology.

[16]  S. Kitamoto,et al.  Interleukin-10 Facilitates Both Cholesterol Uptake and Efflux in Macrophages* , 2009, The Journal of Biological Chemistry.

[17]  I. Tabas.  Macrophage apoptosis in atherosclerosis: consequences on plaque progression and the role of endoplasmic reticulum stress. , 2009, Antioxidants & redox signaling.

[18]  T. V. van Dijk,et al.  Activation of the Liver X Receptor Stimulates Trans-intestinal Excretion of Plasma Cholesterol* , 2009, The Journal of Biological Chemistry.

[19]  K. Ley,et al.  Immune and inflammatory mechanisms of atherosclerosis (*). , 2009, Annual review of immunology.

[20]  G. Kollias,et al.  Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis. , 2008, Cell metabolism.

[21]  Thomas L. Smith,et al.  Targeted Depletion of Hepatic ACAT2-driven Cholesterol Esterification Reveals a Non-biliary Route for Fecal Neutral Sterol Loss* , 2008, Journal of Biological Chemistry.

[22]  F. Kuipers,et al.  Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice. , 2007, Gastroenterology.

[23]  T. Lagerweij,et al.  The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice. , 2007, Atherosclerosis.

[24]  Peter Libby,et al.  The immune response in atherosclerosis: a double-edged sword , 2006, Nature Reviews Immunology.

[25]  V. Deleuze,et al.  In vivo electrotransfer of interleukin-10 cDNA prevents endothelial upregulation of activated NF-kappaB and adhesion molecules following an atherogenic diet. , 2006, European cytokine network.

[26]  S. Tonstad,et al.  Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms Published, JLR Papers in Press, November 16, 2004. DOI 10.1194/jlr.M400324-JLR200 , 2005, Journal of Lipid Research.

[27]  A. Tedgui,et al.  Leukocyte-Derived Interleukin 10 Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[28]  I. van der Made,et al.  Hematopoietic NF-kappaB1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype. , 2004, Blood.

[29]  Georg Kraal,et al.  Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. , 2003, The Journal of clinical investigation.

[30]  D. Tribble,et al.  Inhibition of Intestinal Cholesterol Absorption by Ezetimibe in Humans , 2002, Circulation.

[31]  E. Leiter,et al.  Genetic and environmental context determines the course of colitis developing in IL-10-deficient mice. , 2002, Inflammatory bowel diseases.

[32]  T. Bayer,et al.  Profile of cholesterol-related sterols in aged amyloid precursor protein transgenic mouse brain DOI 10.1194/jlr.M200071-JLR200 , 2002, Journal of Lipid Research.

[33]  M. Fishbein,et al.  Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor–Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes , 2002, Circulation research.

[34]  J. Kuiper,et al.  Attenuation of atherogenesis by systemic and local adenovirus‐mediated gene transfer of interleukin‐10 in LDLr ‐/‐ Mice , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  M. Bureau,et al.  Protective role of interleukin-10 in atherosclerosis. , 1999, Circulation research.

[36]  W. Reith,et al.  Conditional gene targeting in macrophages and granulocytes using LysMcre mice , 1999, Transgenic Research.

[37]  A. Tedgui,et al.  Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[38]  T. Mosmann,et al.  IL-10 inhibits cytokine production by activated macrophages. , 1991, Journal of immunology.

[39]  C G Figdor,et al.  Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes , 1991, The Journal of experimental medicine.

[40]  M. Stanley,et al.  Secretion of Cholesterol by Intestinal Mucosa in Patients with Complete Common Bile Duct Obstruction.∗ , 1959, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[41]  H. Milionis,et al.  An overview of lipid abnormalities in patients with inflammatory bowel disease , 2011, Annals of gastroenterology.

[42]  I. Tabas.  Macrophage death and defective inflammation resolution in atherosclerosis , 2010, Nature Reviews Immunology.

[43]  F. Kuipers,et al.  Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. , 2005, Gastroenterology.

[44]  Y. Kaneda,et al.  Intramuscular gene transfer of interleukin-10 cDNA reduces atherosclerosis in apolipoprotein E-knockout mice. , 2004, Atherosclerosis.

[45]  J. Michel,et al.  Interleukin-10 Deficiency Increases Atherosclerosis, Thrombosis, and Low-density Lipoproteins in Apolipoprotein E Knockout Mice , 2003, Molecular medicine.

[46]  P. Rutgeerts,et al.  Treatment of Crohn's disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon γ , 2002, Gut.

[47]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[48]  N. Lukacs,et al.  Macrophage , 2022, AccessScience.