Effects of Liver X Receptor Agonist Treatment on Pulmonary Inflammation and Host Defense

Laboratory of Respiratory Biology, Department of Health and Human Services, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2008; 180(5):3305-12. DOI: 10.4049/jimmunol.180.5.3305
Source: PubMed


Liver X receptor (LXR) alpha and beta are members of the nuclear receptor superfamily of ligand-activated transcription factors. Best known for triggering "reverse cholesterol transport" gene programs upon their activation by endogenous oxysterols, LXRs have recently also been implicated in regulation of innate immunity. In this study, we define a role for LXRs in regulation of pulmonary inflammation and host defense and identify the lung and neutrophil as novel in vivo targets for pharmacologic LXR activation. LXR is expressed in murine alveolar macrophages, alveolar epithelial type II cells, and neutrophils. Treatment of mice with TO-901317, a synthetic LXR agonist, reduces influx of neutrophils to the lung triggered by inhaled LPS, intratracheal KC chemokine, and intratracheal Klebsiella pneumoniae and impairs pulmonary host defense against this bacterium. Pharmacologic LXR activation selectively modulates airspace cytokine expression induced by both LPS and K. pneumoniae. Moreover, we report for the first time that LXR activation impairs neutrophil motility and identify inhibition of chemokine-induced RhoA activation as a putative underlying mechanism. Taken together, these data define a novel role for LXR in lung pathophysiology and neutrophil biology and identify pharmacologic activation of LXR as a potential tool for modulation of innate immunity in the lung.

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    • "Cardinal features of the disease are airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling [6]. Administration of LXR ligand showed inhibitory roles in lung inflammatory responses [7], [8], [9], [10] and anti-proliferative effects on smooth muscle [11], [12]. LXR also showed therapeutic roles in murine model of allergic contact dermatitis [13]. "
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    ABSTRACT: The liver-X-receptors have shown anti-inflammatory ability in several animal models of respiratory disease. Our purpose is to investigate the effect of LXR ligand in allergen-induced airway remodeling in mice. Ovalbumin-sensitized mice were chronically challenged with aerosolized ovalbumin for 8 weeks. Some mice were administered a LXR agonist, T0901317 (12.5, 25, 50 mg/kg bodyweight) before challenge. Then mice were evaluated for airway inflammation, airway hyperresponsiveness and airway remodeling. T0901317 failed to attenuate the inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid. But the application of T0901317 reduced the thickness of airway smooth muscle and the collagen deposition. Meanwhile, T0901317 treatment evidently abolished the high level of OVA-specific IgE, TGF-β1 and MMP-9 in lung. So LXRs may attenuate the progressing of airway remodeling, providing a potential treatment of asthma.
    PLoS ONE 03/2014; 9(3):e92668. DOI:10.1371/journal.pone.0092668 · 3.23 Impact Factor
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    • "Moreover, this ligand also induced LXRα expression itself at the mRNA and protein levels. These results confirm recent observations that identify neutrophils as target cells for LXR activation in mice [55]. These studies have demonstrated that the expression of LXRα (but not LXRβ) is controlled by an autoregulatory mechanism. "
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    ABSTRACT: Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. They play important roles in controlling cholesterol homeostasis and as regulators of inflammatory gene expression and innate immunity, by blunting the induction of classical pro-inflammatory genes. However, opposite data have also been reported on the consequences of LXR activation by oxysterols, resulting in the specific production of potent pro-inflammatory cytokines and reactive oxygen species (ROS). The effect of the inflammatory state on the expression of LXRs has not been studied in human cells, and constitutes the main aim of the present work. Our data show that when human neutrophils are triggered with synthetic ligands, the synthesis of LXRα mRNA became activated together with transcription of the LXR target genes ABCA1, ABCG1 and SREBP1c. An inflammatory mediator, 15-deoxy-Δ(12,14)-prostaglandin J(2) (15dPGJ(2)), hindered T0901317-promoted induction of LXRα mRNA expression together with transcription of its target genes in both neutrophils and human macrophages. This down-regulatory effect was dependent on the release of reactive oxygen species elicited by 15dPGJ(2), since it was enhanced by pro-oxidant treatment and reversed by antioxidants, and was also mediated by ERK1/2 activation. Present data also support that the 15dPGJ(2)-induced serine phosphorylation of the LXRα molecule is mediated by ERK1/2. These results allow to postulate that down-regulation of LXR cellular levels by pro-inflammatory stimuli might be involved in the development of different vascular diseases, such as atherosclerosis.
    PLoS ONE 10/2012; 7(10):e42195. DOI:10.1371/journal.pone.0042195 · 3.23 Impact Factor
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    • "Activation of LXR has also been shown to reduce inflammation in the aortae of atherosclerotic mice [Joseph et al., 2002] and in a mouse model of contact dermatitis [Fowler et al., 2003]. Recently, the LXR agonists have been shown to suppress lung inflammatory responses via inhibiting the expression of inflammatory genes in alveolar macrophages [Birrell et al., 2007; Smoak et al., 2008]. "
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    ABSTRACT: Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation; key biological processes in atherogenesis. The activation of PPARgamma1 and LXRalpha by natural or synthetic ligands results in the transactivation of ABCA1, ABCG1, and ApoE; integral players in cholesterol efflux and reverse cholesterol transport. In this review, we describe the structure, isoforms, expression pattern, and functional specificity of PPARs and LXRs. Control of PPARs and LXRs transcriptional activity by coactivators and corepressors is also highlighted. The specific roles that PPARgamma1 and LXRalpha play in inducing macrophage cholesterol efflux mediators and antagonizing macrophage inflammatory responsiveness are summarized. Finally, this review focuses on the recently reported regulatory functions that adipocyte enhancer-binding protein 1 (AEBP1) exerts on PPARgamma1 and LXRalpha transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation.
    Nuclear Receptor Signaling 04/2010; 8:e004. DOI:10.1621/nrs.08004
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