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 9

LXR activation suppresses in vitro human Th17 cell differentiation.

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LXR activation suppresses in vitro human Th17 cell differentiation. (A) ...
(A) Human naive CD4+ T cells isolated from the peripheral blood mononuclear cells of a healthy donor were cultured under Th17-inducing conditions for 4 days in the presence of LXR agonists T0901317 (0.5 μM, 1 μM, 2 μM) and GW3965 (2.5 μM, 5 μM, 10 μM) and subjected to the intracellular staining of IL-17 and IFN-γ. Fifteen individual specimens were studied, with similar results. Values in the quadrants indicate the percentage of IL-17+IFN-γ– cells, IL-17+IFN-γ+ cells, and IL-17–IFN-γ+ cells. (B–E) Cells from A were harvested for real-time PCR analysis of the mRNA levels of IL17 (B), IL17F (C), ABCA1 (D), SREBP1 (E), AHR (F), and RORγt (G). The y-axis in B–G represents the relative expression level of genes using arbitrary unit. T0901317 decreased the IL17 (P < 0.01), IL17F (P < 0.01), AHR (P < 0.01), and RORγt (P < 0.05) mRNA levels and increased ABCA1 (P < 0.01) and SREBP1 (P < 0.01). GW3965 suppressed the expression of IL17 (P < 0.01), IL17F (P < 0.01), AHR (P < 0.01), and RORγt (P < 0.05) and increased the mRNA level of ABCA1 (P < 0.01) and SREBP1 (P < 0.01).