Activation of Liver X Receptor Sensitizes Human Dendritic Cells to Inflammatory Stimuli

Törőcsik, Dániel; Baráth, Mónika; Benkő, Szilvia; Széles, Lajos; Dezső, Balázs; Póliska, Szilárd; Hegyi, Zoltán; Homolya, László; Szatmári, István; Lányi, Árpád; Nagy, László

doi:10.4049/jimmunol.0902399

Cited by 63 publications

(51 citation statements)

References 44 publications

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“…6 Similarly, pretreatment with the LXR agonist was shown to sensitize human dendritic cells to LPS stimulation. 7 These differential effects in mouse and human cells were clearly observed in the present study. Indeed and in sharp contrast to human macrophages, LXR treatment significantly decreased eicosanoid secretion in mouse macrophages.…”

Section: Ishibashi Et Al Lxr Regulates Lpcat3 and Arachidonate Metabosupporting

confidence: 75%

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

Ishibashi

Varin

Filomenko

et al. 2013

ATVB

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L iver X receptor-α (LXRα) and LXRβ (Nr1h3 and Nr1h2, respectively) are oxysterol-activated nuclear receptors that regulate the expression of genes involved in different pathways, such as cholesterol and fatty acid (FA) metabolism or inflammation.1 LXRs are attractive targets in the field of atherosclerosis because LXR activation improves cholesterol homeostasis and promotes cholesterol removal from macrophages through the coordinate regulation of apolipoprotein E and the cholesterol transporters ATP-binding cassette transporter A1 and and ATP-binding cassette transporter G1. LXR also stimulates lipogenesis and the production of monounsaturated FAs through induction of prolipogenic genes, including sterol regulatory element-binding protein 1c, FA synthase, and stearoyl CoA desaturase.1 In addition, a specific role for LXR in cellular phospholipid (PL) metabolism was recently described because LXR activation was shown to reduce the biosynthesis of phosphatidylethanolamines by inhibiting the CTP:phosphoethanolamine cytidylyltransferase, an enzyme involved in the Kennedy pathway. 2 Besides cholesterol and FA metabolism, a major function for LXR in macrophages is the control of innate immunity. Treatment of murine macrophages with synthetic LXR agonists attenuates the inflammatory response to lipopolysaccharide (LPS) 3 and it has been demonstrated that LXR ligands can induce the sumoylation of LXR, which subsequently forms complexes with nuclear receptor corepressor 1 and SMRT that inhibit NF-κB-mediated and AP-1-mediated inflammatory response. 4,5 In contrast to mouse macrophages, treatment of human macrophages with © 2013 American Heart Association, Inc. Objective-Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that are highly expressed in macrophages and regulate lipid homeostasis and inflammation. Among putative LXR target genes, lysophosphatidylcholine acyltransferase 3 (LPCAT3) involved in the Lands cycle controls the fatty acid composition at the sn-2 position of glycerophospholipids and, therefore, the availability of fatty acids, such as arachidonic acid (AA), used for eicosanoid synthesis. The aim of our study was to determine whether LXRs could regulate the Lands cycle in human macrophages, to assess the consequences in terms of lipid composition and inflammatory response, and to work out the relative contribution of LPCAT3 to the observed changes. Approach and Results-Transcriptomic analysis revealed that LPCAT3 was upregulated by LXR agonists in human macrophages. Accordingly, LXR stimulation significantly increased lysophospholipid acyltransferase activity catalyzed by LPCAT3. Lipidomic analysis demonstrated that LXR activation increased the AA content in the polar lipid fraction, specifically in phosphatidylcholines. The LXR-mediated effects on AA distribution were abolished by LPCAT3 silencing, and a redistribution of AA toward the neutral lipid fraction was observed in this context. Finally, we observed that preconditioning of human macrophages by LXR agonist treatment increased...

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Section: Ishibashi Et Al Lxr Regulates Lpcat3 and Arachidonate Metabosupporting

confidence: 75%

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

Ishibashi

Varin

Filomenko

et al. 2013

ATVB

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“…LXR-␣ activation takes place upon ligand binding that leads to a molecular switch replacing a corepressor by a coactivator complex ( 35 ). Previous studies showed that adding exogenous synthetic LXR ligands activated the LXR program in monocyte-derived DCs ( 36,37 ). However, our data provide fi rst evidence that LXR-␣ can be transcriptionally active in the presence of IL-17A without exogenously added synthetic ligands.…”

Section: Discussionmentioning

confidence: 51%

Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

Salvatore

Bernoud-Hubac

Bissay

et al. 2015

Journal of Lipid Research

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The emerging fi eld of research called immunometabolism results from mutual interactions between metabolism and immune system. Chronic infl ammation and changes in immune cells participate in metabolic disorders such as atherosclerosis, type 2 diabetes mellitus, and obesity ( 1 ), which are now consequently considered both metabolic and chronic infl ammatory diseases. Conversely, the physiopathological remodeling of cell-intrinsic metabolic pathways modulates the functions of immune cells ( 1, 2 ).Macrophages and dendritic cells (DCs) are antigenpresenting cells, distributed in the tissues as sentinels of the immune system. They play major roles in many pathological conditions, in line with their ability to produce cytokines and

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“…Monocyte-derived dendritic cells (MDDCs) differentiated in the presence of LXR agonists prior to stimulation with TLR ligands released more chemokines and cytokines and showed increased capacity to elicit CD4 + T-cell proliferation [26]. In this case, LXR ligands were replenished regularly throughout differentiation.…”

Section: Responses To Inflammatory Stimulimentioning

confidence: 99%

Liver X receptors in immune cell function in humans

Waddington

Jury

Pineda-Torra

2015

Biochemical Society Transactions

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The liver X receptors (LXRs), LXRα and LXRβ, are transcription factors with well-established roles in the regulation of lipid metabolism and cholesterol homeostasis. In addition, LXRs influence innate and adaptive immunity, including responses to inflammatory stimuli, proliferation and differentiation, migration, apoptosis and survival. However, the majority of work describing the role of LXRs in immune cells has been carried out in mouse models, and there are a number of known species-specific differences concerning LXR function. Here we review what is known about the role of LXRs in human immune cells, demonstrating the importance of these receptors in the integration of lipid metabolism and immune function, but also highlighting the need for a better understanding of the species, isoform, and cell-type specific effects of LXR activation.

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Activation of Liver X Receptor Sensitizes Human Dendritic Cells to Inflammatory Stimuli

Cited by 63 publications

References 44 publications

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

Liver X receptors in immune cell function in humans

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