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LXR? regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8.

ABSTRACT: Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXR? levels are high in regressive plaques. Macrophage arginase 1 (Arg1) expression is inversely correlated with atherosclerosis progression and is markedly decreased in foam cells within the lesion.To investigate LXR? regulation of Arg1 expression in cultured macrophages and atherosclerotic regressive lesions.We found that Arg1 expression is enhanced in CD68+ cells from regressive versus progressive lesions in a murine aortic arch transplant model. In cultured macrophages, ligand-activated LXR? markedly enhances basal and interleukin-4-induced Arg1 mRNA and protein expression as well as promoter activity. This LXR?-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXR?-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXR?-deficient CD68+ cells. LXR? does not bind to the Arg1 promoter but instead promotes the interaction between PU.1 and interferon regulatory factor (IRF)8 transcription factors and induces their binding of a novel composite element. Accordingly, knockdown of either IRF8 or PU.1 strongly impairs LXR? regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXR? binds the IRF8 locus and its activation increases IRF8 mRNA and protein levels in these cells.This work implicates Arg1 in atherosclerosis regression and identifies LXR? as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXR? regulates macrophage target gene expression through PU.1 and IRF8.

SUBMITTER: Pourcet B

PROVIDER: S-EPMC3180895 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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LXRα regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8.

Pourcet Benoit B Feig Jonathan E JE Vengrenyuk Yuliya Y Hobbs Adrian J AJ Kepka-Lenhart Diane D Garabedian Michael J MJ Morris Sidney M SM Fisher Edward A EA Pineda-Torra Inés I

Circulation research 20110714 5

<h4>Rationale</h4>Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXRα levels are high in regressive plaques. Macrophage arginase 1 (Arg1) expression is inversely correlated with atherosclerosis progression and is markedly decreased in foam cells within the lesion.<h4>Objective</h4>To investigate LXRα regulation of Arg1 expression in cultured macrophages and atherosclerotic regressive lesions.<h4>Methods ...[more]

PMID: 21757649

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Project description:Human rhinoviruses (HRV) cause the majority of colds and trigger exacerbations of chronic lower airway diseases. Airway epithelial cells are the primary site for HRV infection and replication, and the initiation of host inflammatory responses. At present, the molecular mechanisms that underpin HRV responses in airway epithelial cells are incompletely understood. The aim of this study was to employ microarray profiling, upstream regulator analysis, and siRNA mediated gene silencing to further our understanding of the role of interferon regulatory factor 7 (IRF7) in this response.Primary human bronchial epithelial cells (HBE) where transfected with siRNA that targets IRF7 or a non-silencing control (all-star control) using Lipofectamine. The cells were allowed to recover, and then cultured in the presence or absence of HRV-16 for 24 h. Global patterns of gene expression were profiled on microarrays. A subset of genes identified in the microarray study were validated at the mRNA and/or protein level using real time RT-qPCR, ELISA, and western blots.Hundreds of genes were upregulated in HBE during HRV infection. Pathways analysis demonstrated that these genes were mainly involved in type I and II interferon signaling, RIG-I/MDA5 signaling, antigen processing and presentation, and apoptosis. Upstream regulator analysis of these data suggested that IRF7 was a major molecular driver of this response. Knockdown of IRF7 reduced the HRV-driven upregulation of genes involved in antiviral responses (interferon signaling, Toll-like receptor signaling, NOD-like receptor signaling, RIG-I/MDA5 signaling), and increased the expression of genes that promote inflammation (e.g. CXCL5, IL-33, IL1RL1) and the response to oxidative stress. However, the majority of genes that were perturbed by HRV in HBE cells including those that are known to be regulated by IRF7 were insensitive to IRF7 knockdown. Upstream regulator analysis of the part of the response that was insensitive to IRF7 knockdown suggested it was driven by NF-?B, STAT1, STAT3, and IRF1.Our findings demonstrate that IRF7 regulates the expression of genes involved in antiviral immunity, inflammation, and the response to oxidative stress during HRV infections in HBE cells, and also suggests that other transcription factors play a major role in this response.

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LXR? regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8.

Publications

LXRα regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8.

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