Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation
Guoliang Cui, … , Jingwu Z. Zhang, Ying Qin Zang
Guoliang Cui, … , Jingwu Z. Zhang, Ying Qin Zang
Published January 25, 2011
Citation Information: J Clin Invest. 2011;121(2):658-670. https://doi.org/10.1172/JCI42974.
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Research Article

Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation

Abstract

Th17 cells are a subset of CD4+ T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+ T cells to IL-6 and TGF-β leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+ T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further analysis revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on the Il17 promoter, physically interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlled Il17 transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Additional analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity.

Authors

Guoliang Cui, Xia Qin, Lili Wu, Yuebo Zhang, Xiaoyan Sheng, Qiwen Yu, Hongguang Sheng, Beili Xi, Jingwu Z. Zhang, Ying Qin Zang

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Figure 1

Oral administration of LXR agonists ameliorates EAE in LXR WT mice but not in LXR KO mice.

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Oral administration of LXR agonists ameliorates EAE in LXR WT mice but n...
(A) EAE was induced in LXR KO mice or WT littermate control mice with or without daily oral administration of LXR agonist from day 3 after immunization to day 17 (6 or 7 mice per group). Data are expressed as mean ± SEM and represent 2 independent experiments with similar results. P = 0.009, WT control versus WT T0901317; P = 0.006, WT control group versus WT GW3965; P = 0.832, KO control versus KO T0901317; P = 0.651, KO control versus KO GW3965; P = 0.039, WT control versus KO control. (B) Maximum (Max) disease was set with a clinical score ≥3. P = 0.002, WT control versus WT T0901317; P = 0.002, WT control versus WT GW3965; P = 0.857, KO control versus KO T0901317; P = 0.807, KO control versus KO GW3965; P = 0.007, WT control versus KO control. (C) Histological staining of spinal cord sections from each group on day 15 after immunization. The white boxes in the upper panels (×4 objective) are enlarged in the lower panels (×10 objective). Total original magnification is ×40 and ×100, respectively.