Increased Antigen Cross-Presentation but Impaired Cross-Priming after Activation of Peroxisome Proliferator-Activated Receptor γ Is Mediated by Up-Regulation of B7H1

Klotz, Luisa; Hucke, Stephanie; Thimm, Dominik; Claßen, Sabine; Gaarz, Andrea; Schultze, Joachim L.; Edenhofer, Frank; Kurts, Christian; Klockgether, Thomas; Limmer, Andreas; Knolle, Percy A.; Burgdorf, Sven

doi:10.4049/jimmunol.0804260

Cited by 38 publications

(30 citation statements)

References 43 publications

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“…Thus, in addition to its functions in lipid metabolism, PPAR␥ may play macrophage-specific roles, such as modulating immune responses with the aid of the hematopoietic factor PU.1. This finding is consistent with recent studies implicating PPAR␥ in the function of alternative macrophages (5,20,55) and bone marrow-derived dendritic cells (34,51).…”

Section: Fig 1 Ppar␥ Binding In Macrophages Compared To Adipocytessupporting

confidence: 82%

“…Thus, the higher protein levels in adipocytes and/or the expression of the ␥2 isoform may allow PPAR␥ to bind and activate a larger number of genes in adipocytes, where it is required for differentiation, mature function, and survival (69). In contrast, macrophages do not require PPAR␥ for differentiation, phagocytic activity, or proinflammatory cytokine production (50) but employ PPAR␥ in more specialized functions, such as maintenance of the alternative macrophage phenotype (5,20,55), cholesterol uptake and efflux in atherosclerotic plaques (49), antigen cross-presentation to T lymphocytes (34), and dendritic cell immunogenicity (51).…”

Section: Discussionmentioning

confidence: 99%

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Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages

Lefterova¹,

Steger²,

Zhuo³

et al. 2010

Molecular and Cellular Biology

189

200

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The nuclear receptor peroxisome proliferator activator receptor ␥ (PPAR␥) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side effects that limit widespread use. PPAR␥ is required for adipocyte differentiation, but it is also expressed in other cell types, notably macrophages, where it influences atherosclerosis, insulin resistance, and inflammation. A central question is whether PPAR␥ binding in macrophages occurs at genomic locations the same as or different from those in adipocytes. Here, utilizing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we demonstrate that PPAR␥ cistromes in mouse adipocytes and macrophages are predominantly cell type specific. In thioglycolate-elicited macrophages, PPAR␥ colocalizes with the hematopoietic transcription factor PU.1 in areas of open chromatin and histone acetylation, near a distinct set of immune genes in addition to a number of metabolic genes shared with adipocytes. In adipocytes, the macrophage-unique binding regions are marked with repressive histone modifications, typically associated with local chromatin compaction and gene silencing. PPAR␥, when introduced into preadipocytes, bound only to regions depleted of repressive histone modifications, where it increased DNA accessibility, enhanced histone acetylation, and induced gene expression. Thus, the cell specificity of PPAR␥ function is regulated by cell-specific transcription factors, chromatin accessibility, and histone marks. Our data support the existence of an epigenomic hierarchy in which PPAR␥ binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation.Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a nuclear receptor that regulates essential aspects of adipocyte biology, including insulin sensitivity, lipogenesis, and survival, and is the target of anti-diabetic thiazolidinedione drugs (39, 69). Recent genome-wide studies of adipocytes (40,53) have demonstrated that PPAR␥ localizes preferentially to lipid and carbohydrate metabolism genes, many of which are downregulated by PPAR␥ knockdown (62). It has also become apparent that in vivo PPAR␥ binding occurs predominantly as a heterodimer with retinoid X receptor (RXR) at direct repeats of the sequence AGGTCA separated by a single base pair, i.e., DR1 elements, as predicted by in vitro studies and a small number of previously known target genes (61). Furthermore, CCAAT/enhancer-binding proteins (C/EBPs) were found to colocalize with PPAR␥ at the majority of its binding sites and to have cooperative effects on target gene transcription (40).The two isoforms of PPAR␥, ␥1 and ␥2, are transcribed from alternative start sites and are most abundant in adipocytes, which require PPAR␥ for differentiation (39, 69), although other cell types express lower levels of the ␥1 isoform (10, 72). Among these, macrophages have garnered much attention for their ability to affect metabolism in a number of tissues...

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Section: Fig 1 Ppar␥ Binding In Macrophages Compared To Adipocytessupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages

Lefterova¹,

Steger²,

Zhuo³

et al. 2010

Molecular and Cellular Biology

189

200

View full text Add to dashboard Cite

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“…Data analysis was carried out by using the Illumina BeadStudio software. Raw data from the present experiment were combined with publicly available pro-B-cell expression data (41), bone marrow-derived dendritic cells (42), and peritoneal macrophages (datasets kindly provided by Amy Sullivan and Christopher K. Glass, University of California, San Diego, CA). The combined raw expression data were normalized by using a mloess algorithm (43).…”

Section: Methodsmentioning

confidence: 99%

Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver

Österreicher

Penz-Österreicher²,

Grivennikov³

et al. 2010

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

304

242

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Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagenproducing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to the myofibroblast population in damaged livers. Fibroblast-specific protein 1 (FSP1, also called S100A4) is considered a marker of fibroblasts in different organs undergoing tissue remodeling and is used to identify fibroblasts derived from EMT in several organs including the liver. The aim of this study was to characterize FSP1-positive cells in human and experimental liver disease. FSP1-positive cells were increased in human and mouse experimental liver injury including liver cancer. However, FSP1 was not expressed by HSC or type I collagenproducing fibroblasts. Likewise, FSP1-positive cells did not express classical myofibroblast markers, including αSMA and desmin, and were not myofibroblast precursors in injured livers as evaluated by genetic lineage tracing experiments. Surprisingly, FSP1-positive cells expressed F4/80 and other markers of the myeloid-monocytic lineage as evaluated by double immunofluorescence staining, cell fate tracking, flow cytometry, and transcriptional profiling. Similar results were obtained for bone marrow-derived and peritoneal macrophages. FSP1-positive cells were characterized by increased expression of COX2, osteopontin, inflammatory cytokines, and chemokines but reduced expression of MMP3 and TIMP3 compared with Kupffer cells/macrophages. These findings suggest that FSP1 is a marker of a specific subset of inflammatory macrophages in liver injury, fibrosis, and cancer.tumor microenvironment

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“…Additionally, studies in humans with type 2 diabetes (T2D) and in rodent models of T2D suggest that TZDs may also directly enhance β cell function (12,13). In addition to their potential effects on β cells, TZDs have also been implicated in the reduction of inflammation and autoimmunity owing to effects on dendritic cells, macrophages, and T cells of the immune system (14)(15)(16).…”

Section: Introductionmentioning

confidence: 98%

Peroxisome Proliferator-activated Receptor-γ Activation Augments the β-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and β Cell Death in Non-obese Diabetic Mice

Maganti

Tersey

Syed

et al. 2016

Journal of Biological Chemistry

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Type 1 diabetes is an autoimmune disorder that is characterized by a failure of the unfolded protein response in islet β cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR-γ and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce β cell stress and death independently of insulin sensitivity. To test this hypothesis, female NOD mice were administered pioglitazone during the pre-diabetic phase and assessed for insulin sensitivity and β cell function relative to controls. Pioglitazone-treated mice showed identical weight gain, body fat distribution, and insulin sensitivity compared with controls. However, treated mice showed significantly improved glucose tolerance with enhanced serum insulin levels, reduced β cell death, and increased β cell mass. The effect of pioglitazone was independent of actions on T cells, as pancreatic lymph node T cell populations were unaltered and T cell proliferation was unaffected by pioglitazone. Isolated islets of treated mice showed a more robust unfolded protein response, with increases in Bip and ATF4 and reductions in spliced Xbp1 mRNA. The effect of pioglitazone appears to be a direct action on β cells, as islets from mice treated with pioglitazone showed reductions in PPAR-γ (Ser-273) phosphorylation. Our results demonstrate that PPAR-γ activation directly improves β cell function and survival in NOD mice by enhancing the unfolded protein response and suggest that blockade of PPAR-γ (Ser-273) phosphorylation may prevent type 1 diabetes.

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Increased Antigen Cross-Presentation but Impaired Cross-Priming after Activation of Peroxisome Proliferator-Activated Receptor γ Is Mediated by Up-Regulation of B7H1

Cited by 38 publications

References 43 publications

Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages

Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages

Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver

Peroxisome Proliferator-activated Receptor-γ Activation Augments the β-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and β Cell Death in Non-obese Diabetic Mice

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