Activation of Liver X Receptor α Sensitizes Mice to T‐Cell Mediated Hepatitis

Li, Gao; Li, Bin; Wang, Jingyuan; Shen, Danhua; Yang, Mengyao; Sun, Runzi; Tung, Hung‐Chun; Xu, Meishu; Zhang, Min; Yang, Da; Lu, Binfeng; Wang, Hui; Liu, Yulan; Xie, Wen

doi:10.1002/hep4.1584

Cited by 7 publications

(8 citation statements)

References 37 publications

(57 reference statements)

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“…In line with our data, a recent study reported that consecutive activation of LXRα exacerbated ConA-induced hepatitis ( 45 ), which supported a pathogenic role of LXRα during AIH development. Additionally, LXRα −/− mice fed with a high-fat and high-cholesterol diet were resistant to ConA due to the dysfunction of invariant NKT cells ( 46 ).…”

Section: Discussionsupporting

confidence: 92%

Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis

Lian

et al. 2021

Front. Immunol.

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Myeloid-derived suppressor cells (MDSCs) emerge as a promising candidate for the immunotherapy of autoimmune hepatitis (AIH). However, targets for modulating MDSC in AIH are still being searched. Liver X receptors (LXRs) are important nuclear receptors linking lipid metabolism and immune responses. Despite the extensive studies of LXR in myeloid compartment, its role in MDSCs is currently less understood. Herein, expression of LXRα was found to be upregulated in AIH patients and colocalized with hepatic MDSCs. In ConA-induced hepatitis, deletion of LXRα led to increased expansion of MDSCs in the liver and alleviated the hepatic injury. MDSCs in LXRα−/− mice exhibited enhanced proliferation and survival comparing with WT mice. T-cell proliferation assay and adoptive cell transfer experiment validated the potent immunoregulatory role of MDSCs in vitro and in vivo. Mechanistically, MDSCs from LXRα−/− mice possessed significantly lower expression of interferon regulatory factor 8 (IRF-8), a key negative regulator of MDSC differentiation. Transcriptional activation of IRF-8 by LXRα was further demonstratedConclusionWe reported that abrogation of LXRα facilitated the expansion of MDSCs via downregulating IRF-8, and thereby ameliorated hepatic immune injury profoundly. Our work highlights the therapeutic potential of targeting LXRα in AIH.

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Section: Discussionsupporting

confidence: 92%

Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis

Lian

et al. 2021

Front. Immunol.

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“…In line with our data, a recent study reported that consecutive activation of LXRa exacerbated ConA-induced hepatitis (45), which supported a pathogenic role of LXRa during AIH development. Additionally, LXRa −/− mice fed with a high-fat and high-cholesterol diet were resistant to ConA due to the dysfunction of invariant NKT cells (46).…”

Section: Discussionsupporting

confidence: 92%

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“…The percentage of iNKT cells in hepatic MNCs is decreased in LXRα-KO mice fed high-fat and high-cholesterol diet and the response to α-GalCer is impaired in these mice 18 . Con-A-induced hepatitis is attenuated in LXRα-KO mice and is exacerbated in constitutively active LXRα knock-in mice 33 . These findings indicate that LXRα and also LXRβ are involved in hepatic iNKT cell-mediated immune responses.…”

Section: Discussionmentioning

confidence: 96%

Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice

Endo-Umeda

Nakashima

Uno

et al. 2021

Sci Rep

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The nuclear receptors liver X receptor α (LXRα) and LXRβ are lipid sensors that regulate lipid metabolism and immunity. Natural killer T (NKT) cells, a T cell subset expressing surface markers of both natural killer cells and T lymphocytes and involved in antitumor immunity, are another abundant immune cell type in the liver. The potential function of the metabolic regulators LXRα/β in hepatic NKT cells remains unknown. In this study, we examined the role of LXRα and LXRβ in NKT cells using mice deficient for LXRα and/or LXRβ, and found that hepatic invariant NKT (iNKT) cells are drastically decreased in LXRα/β-KO mice. Cytokine production stimulated by the iNKT cell activator α-galactosylceramide was impaired in LXRα/β-KO hepatic mononuclear cells and in LXRα/β-KO mice. iNKT cell-mediated antitumor effect was also disturbed in LXRα/β-KO mice. LXRα/β-KO mice transplanted with wild-type bone marrow showed decreased iNKT cells in the liver and spleen. The thymus of LXRα/β-KO mice showed a decreased population of iNKT cells. In conclusion, LXRα and LXRβ are essential for NKT cell-mediated immunity, such as cytokine production and hepatic antitumor activity, and are involved in NKT cell development in immune tissues, such as the thymus.

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Activation of Liver X Receptor α Sensitizes Mice to T‐Cell Mediated Hepatitis

Cited by 7 publications

References 37 publications

Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis

Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis

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Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice

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