Editors' ChoiceMETABOLISM AND AUTOIMMUNITY

Grease fires turn up the heat in autoimmune disease

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Science Translational Medicine  25 Jan 2017:
Vol. 9, Issue 374, eaal4997
DOI: 10.1126/scitranslmed.aal4997

Abstract

Restoring reverse cholesterol transport ameliorates the B cell hyperexpansion and autoimmune disease found to be associated with accumulation of cholesterol in CD11c+ antigen–presenting cells.

The binding of oxygenated cholesterol in cells by the ubiquitously expressed liver X receptor (LXR) nuclear transcription factors activates reverse transport of cholesterol from the periphery to the liver. Although it is known that regulation of cellular cholesterol levels and the presence of LXRs are important for macrophage function, little is known about how this pathway affects other immune cells. In a new study, Ito et al. provide insights into how excess cellular cholesterol can influence adaptive autoimmunity.

A key experimental strategy was to increase systemic cholesterol levels in mice by combining a defect in reverse transport induced by genetic deletion of LXRβ, with either genetic deletion of the low density lipoprotein receptor ligand ApoE or a Western diet. In this setting of increased lymph node cholesterol, there was expansion of B cells and CD11c+ MHC class II+ cells—which include dendritic cells (DCs) and other antigen-presenting cells (APCs)—and evidence of autoimmune disease in the kidneys. They demonstrated that lymph node CD11c+ APCs from Apoe–/– Lxrb–/– and Western diet–fed Lxrb–/– mice had elevated gene expression levels of Baff and April, which are tumor necrosis factor family members known to support B cell expansion and autoimmune disease. Additionally, CD11c+ MHC class II+ APCs overloaded with cholesterol also had enhanced ability to present antigen to T cells.

They exploited these mechanisms therapeutically by in vitro reduction of membrane cholesterol in DCs or treatment of DCs with the synthetic LXR agonist GW3965, both of which reduced Baff and April gene expression. In vivo adenoviral vector–mediated increase in systemic ApoA-I, which facilitates cellular efflux of cholesterol as the primary protein constituent of high density lipoprotein (HDL), resulted in abrogation of B cell expansion and normalization of lymph node and spleen Baff and April expression. As all of these studies were performed in mice lacking LXRβ activity, confirmation of pathology through other means of increasing CD11c+ cell cholesterol is needed to validate the proposed pathways to autoimmunity. Nonetheless, given the complexity of the emerging scientific area of metabolism and immunity, it is remarkable how much the evidence base has grown for the hypothesis that autoimmune disease can be treated by augmenting reverse cholesterol transport—either by increasing HDL (e.g., through statins) or more directly by targeting LXRs—and by lifestyle modifications including diet, physical activity, and weight loss.

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