Apolipoprotein E promotes immune suppression in pancreatic cancer through NF-kB-mediated production of CXCL1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE160592 | GEO | 2021/05/12
REPOSITORIES: GEO
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Project description:Apolipoprotein E promotes immune suppression in pancreatic cancer through NF-kB-mediated production of CXCL1
| PRJNA673706 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the stroma and are key drivers of immunosuppression. TAMs in human and murine PDAC are characterized by elevated expression of apolipoprotein E (ApoE), an apolipoprotein that mediates cholesterol metabolism and has known roles in cardiovascular and Alzheimer's disease but no known role in PDAC. We report here that ApoE is also elevated in peripheral blood monocytes in PDAC patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDAC cells into syngeneic wild-type or in ApoE-/- mice showed reduced tumor growth in ApoE-/- mice. Histologic and mass cytometric (CyTOF) analysis of these tumors showed an increase in CD8+ T cells in tumors in ApoE-/- mice. Mechanistically, ApoE induced pancreatic tumor cell expression of Cxcl1 and Cxcl5, known immunosuppressive factors, through LDL receptor and NF-κB signaling. Taken together, this study reveals a novel immunosuppressive role of ApoE in the PDAC microenvironment. SIGNIFICANCE: This study shows that elevated apolipoprotein E in PDAC mediates immune suppression and high serum apolipoprotein E levels correlate with poor patient survival.See related commentary by Sherman, p. 4186.
| S-EPMC8445065 | biostudies-literature
Project description:Apolipoprotein E (apoE) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). In the brain, apoE is predominantly expressed and secreted by astrocytes, but is dramatically up-regulated in microglia under AD-associated conditions. Although the function of astrocytic apoE has been widely investigated, whether and how apoE particles derived from different types of glia differ in biological features and function remains elusive. Here, we show that apoE particles derived from astrocytes and microglia exhibit dissimilar sizes. Microglial apoE particles impaired neurite growth and synapses and promoted neuronal senescence, whereas GPNMB-deficient microglial apoE particles abolished these detrimental effects. These findings provide direct evidence supporting that microglia-derived apoE particles contribute to neuronal senescence and toxicity.
2024-06-28 | GSE246888 | GEO
Project description:The anti-diabetic drug and agonist of the peroxisome proliferator-activated receptor gamma (Pparg), rosiglitazone, was recently withdrawn in many countries because the drug use was associated with an increased risk of heart failure. To investigate underlying pathomechanisms, we chose 6-month-old apolipoprotein E (apoE)-deficient mice, which are prone to atherosclerosis and insulin resistance, and thereby mimic the risk profile of patients with cardiovascular disease. After 8 weeks of rosiglitazone treatment (30 mg/kg/day), echocardiography and histology analyses demonstrated that rosiglitazone had induced heart failure with cardiac dilation. Concomitantly, cardiac lipid overload and lipid-induced cardiomyocyte death developed. The microarray gene expression study of heart tissue from rosiglitazone-treated apoE-deficient mice relative to untreated apoE-deficient mice and non-transgenic B6 mice identified cardiac Pparg-dependent lipid metabolism genes in rosiglitazone-treated mice, which seem to trigger a major heart failure promoting pathway. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) rosiglitazone-treated 8-month-old apolipoprotein (apoE)-deficient mice with symptoms of heart failure, (ii) untreated 8-month-old apoE-deficient mice, and (iii) age-matched, untreated, non-transgenic B6 control mice.
2011-03-18 | E-GEOD-28031 | biostudies-arrayexpress
Project description:Objective: Apolipoprotein E (Apo E) is a multifunctional protein, originally described in the context of lipoprotein metabolism and cardiovascular disease. More recently, anti-inflammatory functions of ApoE have been documented. ApoE was studied in the context of several inflammatory disorders, but its role in the pathogenesis of acute organ rejection is unknown. In this study, we test the hypothesis that ApoE attenuates acute renal allograft rejection. Materials and methods: The Dark Agouti (DA) to Lewis (Lew) and the Brown Norway (BN) to Lew rat strain combinations were used to investigate fatal acute rejection. In addition, Fischer 344 (F344) kidneys were transplanted to Lew rats to study reversible acute rejection. Isograft recipients and untreated Lew rats were used as controls. ApoE mRNA expression was quantified in intravascular leukocytes accumulating in the blood vessels of renal grafts and in graft tissue. Apo E protein levels were assessed in blood plasma. To test the protective potential of ApoE, recipients of BN kidneys were treated with ApoE-mimetic peptide. Results: Intravascular graft leukocytes and renal tissue obtained from animals undergoing reversible acute rejection expressed increased levels of ApoE mRNA, whereas during fatal rejection, ApoE expression remained unchanged in the BN to Lew rat strain combination or was significantly reduced when DA rats were used as donors of the kidney. On the protein level, no changes in ApoE were seen in plasma. However, we do not know if local leukocytic ApoE expression results in increased ApoE concentrations inside graft blood vessels. Peptide treatment of allograft recipients reversed fatal rejection and significantly improved animal survival. Conclusions: ApoE plays a protective role in acute organ rejection. Further studies are needed to understand the exact mechanism how ApoE reverses acute rejection. dual-color balanced dye-swap design with 4 biological replicates, hybridized on 4 arrays
2016-06-01 | E-GEOD-58156 | biostudies-arrayexpress
Project description:Apolipoprotein E (APOE) is a lipid and cholesterol transport molecule known to influence Alzheimer's disease (AD) risk in an isoform-specific manner. In particular, the APOE E4 allele is the largest genetic risk factor for late-onset sporadic AD. Our recent findings uncovered activated, clonally expanded T cells in AD cerebrospinal fluid (CSF). This T cell phenotype occurred concomitantly with altered expression of APOE in CSF monocytes. Yet, whether APOE variants differentially affect peripheral immunity systems remains unknown. In this study, we performed targeted immune profiling using single-cell epigenetic and transcriptomic analysis of peripheral blood mononuclear cells (PBMC). We analyzed 55 age-matched healthy control (HC) and AD patients with equal distribution of APOE E3/E3, E3/E4, and E4/E4 genotypes. We reveal dysregulation in monocytes and clonally expanded T cells that are distinct to AD patients carrying the APOE E4/E4 genotype. Additionally, we find APOE isoform-dependent chromatin accessibility differences that correspond to RNA expression changes. Cumulatively, these results uncover APOE isoform-dependent changes to peripheral immunity in AD.
2024-03-22 | GSE227991 | GEO
Project description:To gain insight into how CXCL1 activation of CXCR2 regulates the expression of stemness and differentiation markers, RNAseq analysis was performed on normal human epidermal melanocyte (NHEM) cultures treated with CXCL1 or with CXCL1 and SX-682.
2023-06-07 | GSE223285 | GEO
Project description:Acetaminophen (APAP) overdose is the major cause of drug-induced liver injury (DILI) and acute liver failure (ALF), and patients with advanced APAP toxicity rarely benefit from N-acetylcysteine (NAC), which is the first-line agent used in the clinic. Mesenchymal stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have shown promising effects in the treatment of DILI by decreasing neutrophil infiltration. However, the specific mechanism underlying the therapeutic effects of MSCs or MSC-EVs still needs to be elucidated. In this study, by using RNA-seq, we found that CXCL1, which is a chemoattractant for neutrophils, is a key molecule in MSC-mediated amelioration of DILI, and by luciferase reporter assay, we verified that MSC-EV-derived miR-186-5p binds to the 3’-UTR of CXCL1 to inhibit its expression in hepatocytes. Neutralizing CXCL1 reduces APAP-induced liver damage in vivo, and the agomir miR-186-5p shows excellent potential in the treatment of DILI. Overall, these findings suggest that the use of MSC-EVs may be a promising novel strategy for preventing DILI and that targeting the miR-186-5P/CXCL1 axis is a feasible approach for improving the efficacy of MSCs in the treatment of DILI.
2024-11-13 | GSE252192 | GEO
Project description:Objective: Apolipoprotein E (Apo E) is a multifunctional protein, originally described in the context of lipoprotein metabolism and cardiovascular disease. More recently, anti-inflammatory functions of ApoE have been documented. ApoE was studied in the context of several inflammatory disorders, but its role in the pathogenesis of acute organ rejection is unknown. In this study, we test the hypothesis that ApoE attenuates acute renal allograft rejection. Materials and methods: The Dark Agouti (DA) to Lewis (Lew) and the Brown Norway (BN) to Lew rat strain combinations were used to investigate fatal acute rejection. In addition, Fischer 344 (F344) kidneys were transplanted to Lew rats to study reversible acute rejection. Isograft recipients and untreated Lew rats were used as controls. ApoE mRNA expression was quantified in intravascular leukocytes accumulating in the blood vessels of renal grafts and in graft tissue. Apo E protein levels were assessed in blood plasma. To test the protective potential of ApoE, recipients of BN kidneys were treated with ApoE-mimetic peptide. Results: Intravascular graft leukocytes and renal tissue obtained from animals undergoing reversible acute rejection expressed increased levels of ApoE mRNA, whereas during fatal rejection, ApoE expression remained unchanged in the BN to Lew rat strain combination or was significantly reduced when DA rats were used as donors of the kidney. On the protein level, no changes in ApoE were seen in plasma. However, we do not know if local leukocytic ApoE expression results in increased ApoE concentrations inside graft blood vessels. Peptide treatment of allograft recipients reversed fatal rejection and significantly improved animal survival. Conclusions: ApoE plays a protective role in acute organ rejection. Further studies are needed to understand the exact mechanism how ApoE reverses acute rejection.
2016-06-01 | GSE58156 | GEO
Project description:The anti-diabetic drug and agonist of the peroxisome proliferator-activated receptor gamma (Pparg), rosiglitazone, was recently withdrawn in many countries because the drug use was associated with an increased risk of heart failure. To investigate underlying pathomechanisms, we chose 6-month-old apolipoprotein E (apoE)-deficient mice, which are prone to atherosclerosis and insulin resistance, and thereby mimic the risk profile of patients with cardiovascular disease. After 8 weeks of rosiglitazone treatment (30 mg/kg/day), echocardiography and histology analyses demonstrated that rosiglitazone had induced heart failure with cardiac dilation. Concomitantly, cardiac lipid overload and lipid-induced cardiomyocyte death developed. The microarray gene expression study of heart tissue from rosiglitazone-treated apoE-deficient mice relative to untreated apoE-deficient mice and non-transgenic B6 mice identified cardiac Pparg-dependent lipid metabolism genes in rosiglitazone-treated mice, which seem to trigger a major heart failure promoting pathway.
2011-03-18 | GSE28031 | GEO