Liver X receptors in immune cell function in humans

Waddington, Kirsty E.; Jury, Elizabeth C.; Pineda-Torra, Inés

doi:10.1042/bst20150112

Cited by 26 publications

(21 citation statements)

References 49 publications

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“…Little is known about the mechanisms underlying these species-specific differences. Possible explanations included the differential regulation of TLR4 or lysophosphatidylcholine acyltransferase 3 (39). Our study now extends these observations and provides novel mechanistic data demonstrating LXR dependent metabolic and epigenetic modulation as key factors in this context.…”

Section: Discussionsupporting

confidence: 76%

LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes

et al. 2020

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Objectives: The concept of trained innate immunity describes a long-term proinflammatory memory in innate immune cells. Trained innate immunity is regulated through reprogramming of cellular metabolic pathways including cholesterol and fatty acid synthesis. Here, we have analyzed the role of Liver X Receptor (LXR), a key regulator of cholesterol and fatty acid homeostasis, in trained innate immunity. Methods and Results: Human monocytes were isolated and incubated with different stimuli for 24 h, including LXR agonists, antagonists and Bacillus Calmette-Guerin (BCG) vaccine. After 5 days resting time, cells were restimulated with the TLR2agonist Pam3cys. LXR activation did not only increase BCG trained immunity, but also induced a long-term inflammatory activation by itself. This inflammatory activation by LXR agonists was accompanied by characteristic features of trained innate immunity, such as activating histone marks on inflammatory gene promoters and metabolic reprogramming with increased lactate production and decreased oxygen consumption rate. Mechanistically, LXR priming increased cellular acetyl-CoA levels and was dependent on the activation of the mevalonate pathway and IL-1β signaling. In contrast to mevalonate pathway inhibition, blocking fatty acid synthesis further increased proinflammatory priming by LXR. Conclusion: We demonstrate that LXR activation induces a proinflammatory trained immunity phenotype in human monocytes through epigenetic and metabolic reprogramming. Our data reveal important novel aspects of LXR signaling in innate immunity.

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Section: Discussionsupporting

confidence: 76%

LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes

et al. 2020

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“…). This supports that the immunomodulatory effects of LXR activation vary between celltypes and species 23 .…”

Section: Fig S1fsupporting

confidence: 78%

“…However, we detected an increase in the production of both IL-2 and IL-4 and, in contrast to previous studies, did not observe inhibition of IFN-γ or TNF-α. Because the anti-inflammatory actions of LXR are context dependent 35,40,57 , it is likely that differences in the conditions for T cell stimulation or LXR activation could explain this discrepancy. In addition, age and sex can both influence LXR signalling 58,59 .…”

Section: Discussionmentioning

confidence: 99%

LXR alters CD4⁺ T cell function through direct regulation of glycosphingolipid synthesis

Waddington

Robinson

Rubio-Cuesta

et al. 2019

Preprint

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Liver X Receptors (LXRs) are important transcriptional regulators of intracellular cholesterol, fatty acid, and phospholipid levels. LXRs can dampen inflammation in macrophages by promoting cholesterol efflux and altering plasma membrane lipid rafts; microdomains enriched for cholesterol and glycosphingolipids that regulate immune-cell signalling. However, little is known about the impact of LXR activators on T cell plasma membrane lipid rafts, which are critical for T-cell antigen receptor (TCR) signalling. Here we show that the LXR synthetic agonist GW3965 significantly increases glycosphingolipid levels and reduces cholesterol and lipid order (stability) in the plasma membrane of human CD4 + T cells. Moreover, the GSL biosynthesis enzyme UGCG was identified as a novel direct target of LXR activation. Importantly, LXR-mediated changes in T cell lipid composition were associated with altered spatiotemporal distribution of lipids and signalling molecules at the immune synapse. Crucially, LXR activation altered the kinetics of proximal TCR-signalling events in activated T cells, reduced T cell proliferation and enhanced the production of IL-2 and IL-4. Thus, LXR activation influences T cell function via alteration of the plasma membrane lipid profile. Finally, the expression of UGCG and other LXR-regulated genes and lipids was significantly dysregulated in T-cells isolated from people with multiple sclerosis. Overall, a novel action of LXR has been characterised that involves modulation of lipid raft-associated cholesterol and glycosphingolipids in CD4 + T-cells, which could be of therapeutic relevance in multiple sclerosis. Keywords liver X receptor -CD4 + T cell -lipid metabolismcholesterolglycosphingolipid-multiple sclerosis 3

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“…47e50 Macrophages are the most studied cells with respect to the LXR actions on immunity and were the first cell types in which the anti-inflammatory effects of LXRs were recognized. 28,51 To ascertain whether retinal environment and knockout genotypes have specific effects on the gene expression in microglia/macrophages, both RMM and BMDM from five genetic lines were evaluated: two wild-type strains (C57BL/6J and C57BL/6J;129S6/ SvEv) and three knockout genotypes (Cyp46a1 À/À , Cyp27a1 À/À , and Cyp27a1 À/À Cyp46a1 À/À ) (Figure 7).…”

Section: Basal Gene Expression In Macrophagesmentioning

confidence: 99%

Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in Cytochrome P450 46A1–Mediated Cholesterol Removal

Saadane

Mast

Trichonas

et al. 2019

The American Journal of Pathology

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Liver X receptors in immune cell function in humans

Cited by 26 publications

References 49 publications

LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes

LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes

LXR alters CD4⁺ T cell function through direct regulation of glycosphingolipid synthesis

Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in Cytochrome P450 46A1–Mediated Cholesterol Removal

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Liver X receptors in immune cell function in humans

Cited by 26 publications

References 49 publications

LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes

LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes

LXR alters CD4+ T cell function through direct regulation of glycosphingolipid synthesis

Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in Cytochrome P450 46A1–Mediated Cholesterol Removal

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LXR alters CD4⁺ T cell function through direct regulation of glycosphingolipid synthesis