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

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.


http://ift.tt/2hFNaaP