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Τρίτη 20 Δεκεμβρίου 2016

Cholesterol Accumulation in CD11c+ Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease

Publication date: 20 December 2016
Source:Immunity, Volume 45, Issue 6
Author(s): Ayaka Ito, Cynthia Hong, Kazuhiro Oka, Jon V. Salazar, Cody Diehl, Joseph L. Witztum, Mercedes Diaz, Antonio Castrillo, Steven J. Bensinger, Lawrence Chan, Peter Tontonoz
Liver X receptors (LXRs) are regulators of cholesterol metabolism that also modulate immune responses. Inactivation of LXR α and β in mice leads to autoimmunity; however, how the regulation of cholesterol metabolism contributes to autoimmunity is unclear. Here we found that cholesterol loading of CD11c+ cells triggered the development of autoimmunity, whereas preventing excess lipid accumulation by promoting cholesterol efflux was therapeutic. LXRβ-deficient mice crossed to the hyperlipidemic ApoE-deficient background or challenged with a high-cholesterol diet developed autoantibodies. Cholesterol accumulation in lymphoid organs promoted T cell priming and stimulated the production of the B cell growth factors Baff and April. Conversely, B cell expansion and the development of autoantibodies in ApoE/LXR-β-deficient mice was reversed by ApoA-I expression. These findings implicate cholesterol imbalance as a contributor to immune dysfunction and suggest that stimulating HDL-dependent reverse cholesterol transport could be beneficial in the setting of autoimmune disease.

Graphical abstract

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Teaser

Ito et al. show that dietary lipid excess and impairment of cholesterol efflux accelerate the development of autoimmunity. Accumulation of cholesterol in CD11c+ APCs promotes BAFF and April production and enhances antigen presentation, contributing to the development of autoimmune-related pathology. Conversely, promoting reverse cholesterol transport through ApoA-I expression ameliorates autoimmunity.


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