Nuclear receptors in human immune cells: Expression and correlations

Schote, Andrea B.; Turner, Jonathan D.; Schiltz, Jang; Muller, Claude P.

doi:10.1016/j.molimm.2006.04.021

Cited by 126 publications

(98 citation statements)

References 30 publications

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“…TR4 is also highly expressed in immune cells and macrophages. However, its roles within the macrophage remain unknown (27,28).Given the facts on TR4 circadian expression profiles, the similarly of its DNA responsive element with PPAR, and the complexity of CD36 in regulating of lipid metabolism, we hypothesize that TR4 is another nuclear receptor that may function as a fatty acid sensor to modulate the CD36-mediated lipid metabolism process. Here we identify a previously undescribed signaling pathway in which TR4 regulates CD36-mediated foam cell formation.…”

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confidence: 99%

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TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation

Xie

Lee

Kim

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

117

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Testicular orphan nuclear receptor 4 (TR4) is an orphan member of the nuclear receptor superfamily with diverse physiological functions. Using TR4 knockout (TR4 ؊/؊ ) mice to study its function in cardiovascular diseases, we found reduced cluster of differentiation (CD)36 expression with reduced foam cell formation in TR4 ؊/؊ mice. Mechanistic dissection suggests that TR4 induces CD36 protein and mRNA expression via a transcriptional regulation. Interestingly, we found this TR4-mediated CD36 transactivation can be further enhanced by polyunsaturated fatty acids (PUFAs), such as omega-3 and -6 fatty acids, and their metabolites such as 15-hydroxyeico-satetraonic acid (15-HETE) and 13-hydroxy octa-deca dieonic acid (13-HODE) and thiazolidinedione (TZD)-rosiglitazone. Both electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrate that TR4 binds to the TR4 response element located on the CD36 5 -promoter region for the induction of CD36 expression. Stably transfected TR4-siRNA or functional TR4 cDNA in the RAW264.7 macrophage cells resulted in either decreased or increased CD36 expression with decreased or increased foam cell formation. Restoring functional CD36 cDNA in the TR4 knockdown macrophage cells reversed the decreased foam cell formation. Together, these results reveal an important signaling pathway controlling CD36-mediated foam cell formation/cardiovascular diseases, and findings that TR4 transactivation can be activated via its ligands/activators, such as PUFA metabolites and TZD, may provide a platform to screen new drug(s) to battle the metabolism syndrome, diabetes, and cardiovascular diseases.A therosclerosis is a disease of both lipid disorder and chronic inflammation that results from interactions of modified lipoproteins, monocyte-derived macrophages, T cells, and cells from the vessel wall (1). Foam cell formation has a central role in the pathogenesis of atherosclerosis. Uptake of oxidized forms of low-density lipoproteins (oxLDL) induces macrophage maturation to form foam cells, which lead to the fatty streaks characteristic of early atherosclerosis. This uptake is mediated by specific macrophage scavenger receptors, including cluster of differentiation (CD)36 (2) and scavenger receptor A (SRA) (3), which recognize and internalize modified lipoproteins such as oxLDL. Among these 2 SRAs, CD36 accounts for a large proportion of oxLDL uptake by macrophages (4-7). Combined inhibition of SRA and CD36 blocks human and mouse foam cell formation in vitro, yet human subjects carrying CD36 mutation usually have a higher risk for atherosclerosis. CD36 roles in oxLDL-mediated foam cell formation in vitro are clear, but its roles in atherosclerosis in vivo are equivocal, which can be either atherogenic (6-8) or atheroprotective (9-11).Peroxisome proliferator-activated receptor (PPAR)␥ is one of the major CD36 upstream regulators in which PPAR␥/retinoid X receptor (RXR) can bind to DNA responsive elements on its 5Ј-promoter to modulate CD36 gene expression (12)....

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mentioning

confidence: 99%

“…TR4 is also highly expressed in immune cells and macrophages. However, its roles within the macrophage remain unknown (27,28).…”

mentioning

confidence: 99%

TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation

Xie

Lee

Kim

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

117

View full text Add to dashboard Cite

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“…In this study, we investigate host-pathogen interactions, particularly those between host lipid-sensing nuclear receptors (LSNRs) and pathogen lipids, that contribute to M. tuberculosis pathogenesis or clearance. Our approach is to look beyond NF-kB to other nuclear receptors that have recently been reported to be expressed and function in macrophages and other immune cells (1,2). We also look beyond the interactions of M. tuberculosis-associated lipids with membrane receptors, such as TLRs, non-TLRs, and opsonic receptors (3,4), to the lipids' ability to modulate host LSNRs for M. tuberculosis pathogenesis and survival.…”

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confidence: 99%

Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival

Mahajan

Dkhar

Chandra

et al. 2012

The Journal of Immunology

166

195

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Mycobacterium tuberculosis–macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis–macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.

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“…The AhR is mainly expressed in liver cells, but it is also present in blood cells (Prigent et al, 2014;Schote et al, 2007;Siest et al, 2008). Also, an induction of the cytochromes P450 1A1 (CYP1A1) and 1B1 (CYP1B1) mRNA expression as AhR activation markers has been observed in blood cells (Prigent et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

DDE and PCB 153 independently induce aryl hydrocarbon receptor (AhR) expression in peripheral blood mononuclear cells

Gaspar-Ramírez

Pérez‐Vázquez

Salgado‐Bustamante³

et al. 2014

Journal of Immunotoxicology

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Recent studies have demonstrated that compounds inducing pro-inflammatory cytokines enhance AhR expression. The aim of this study was 2-fold: (1) to determine if two pro-inflammatory compounds, dichlorodiphenyldichloroethylene (DDE) and 2,2 0 ,4,4 0 ,5,5 0 -hexa-chlorobiphenyl (PCB 153), independently affect AhR gene expression in peripheral blood mononuclear cells (PBMC); and (2) if affected, to determine whether the mechanism involved was due to AhR activation or to a pro-inflammatory effect of the chemicals. PBMC isolated from healthy individuals were incubated in the presence of DDE (10 mg/ml) and PCB 153 (20 ng/ml) over time and AhR and CYP1A1 expression was assessed with a real-time PCR technique. The results indicated there was over-expression of the AhR mRNA in PBMC when the cells were treated with DDE and PCB 153. No changes in expression levels of CYP1A1 mRNA were found. Importantly, when the cells were exposed to DDE and PCB 153 in the presence of an antagonist of tumor necrosis factor (TNF)-, the over-expression of AhR was abolished; as expected, the expression of CYP1A1 was unaffected. In conclusion, these studies demonstrated for the first time an increment of AhR expression ''in vitro'' in PBMC treated with two pro-inflammatory environmental pollutants, DDE and PCB153. Moreover, the over-expression of AhR was dependent of TNF induced by DDE and PCB 153 and was independent of AhR activation.

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Nuclear receptors in human immune cells: Expression and correlations

Cited by 126 publications

References 30 publications

TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation

TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation

Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival

DDE and PCB 153 independently induce aryl hydrocarbon receptor (AhR) expression in peripheral blood mononuclear cells

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