Nanostring of gene expression in intrahepatic leukocytes from mouse fed a chow or high-fat, -fructose, and -cholesterol (FFC) diet and treated with vehicle or a pharmacological inhibitor of the receptor for advanced glycation end products (RAGE), TTP488
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PROVIDER: PRJNA1017609 | ENA |
REPOSITORIES: ENA
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Project description:Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte derived macrophages. RAGE is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that a subset of RAGE expressing macrophages are proinflammatory and mediate liver inflammation in NASH. We profiled the transcriptome of intrahepatic leukocytes in a murine model of diet induced NASH in WT and RAGE-MKO mice. By Nanostring nCounter Immunology Codeset Analysis of IHLs, we observed that myeloid-specific RAGE deletion resulted in amelioration of activation of macrophage and T cell pathways which was associated with attenuation of liver inflammation.
2023-09-15 | GSE243294 | GEO
Project description:Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte derived macrophages. RAGE is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that a subset of RAGE expressing macrophages are proinflammatory and mediate liver inflammation in NASH. We profiled the transcriptome of intrahepatic leukocytes in a murine model of diet induced NASH where mice received vehicle or a pharmacological RAGE inhibitor (TTP488). By Nanostring nCounter Immunology Codeset Analysis of IHLs, we observed that RAGE inhibition resulted in amelioration of FFC diet induced activation of macrophage and T cell pathways which was associated with attenuation of liver inflammation.
2023-09-15 | GSE243293 | GEO
Project description:Nanostring of gene expression in intrahepatic leukocytes from wild type (WT) or myeloid-specific RAGE knockout (RAGE-MKO) mice fed a chow or high-fat, -fructose, and -cholesterol (FFC) diet
| PRJNA1017610 | ENA
Project description:Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with increased risk of fibrosis and liver failure. The Receptor for Advanced Glycation End Products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remains elusive. In this study, we aimed to delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we revealed the central role of BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.
2025-01-07 | GSE275751 | GEO
Project description:Epithelial-Mesenchymal plasticity plays a fundamental role both in embryogenesis and in tumor cell dissemination during tumor progression. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL. We uncover a crosstalk mechanism between the TGF-β and RAGE pathways that is required for the acquisition of mesenchymal traits in TNBC cells. Consistently, RAGE inhibition elicits epithelial features that block migration and invasion capacities. Since RAGE is a sensor of the tumor microenvironment (TME) and the highly glycolytic rate of tumors induces an acidic TME, we modeled acute acidosis in TNBC cells and showed it promotes enhanced production of RAGE ligands and the activation of RAGE-dependent invasive properties. Furthermore, acute acidosis increases SNAIL levels and tumor cell invasion in a RAGE-dependent manner. Finally, we demonstrate that in vivo inhibition of RAGE reduces metastasis incidence and expands survival, consistent with molecular effects that support the relevance of RAGE signaling in EMT plasticity. These results uncover new molecular insights on the regulation of EMT phenotypes in cancer metastasis and provide rationale for pharmacological intervention of this signaling axis.
2023-12-28 | GSE223229 | GEO
Project description:Cardiac aging is characterized by increased cardiomyocyte hypertrophy, myocardial stiffness and fibrosis, which enhance the cardiovascular risk. The receptor for advanced glycation end-products (RAGE) is involved in several age-related diseases. Rage knockout (Rage-/-) mice show an acceleration of cardiac dimensions changes and interstitial fibrosis with aging. This study identifies the age-associated cardiac gene expression signature induced by RAGE deletion. We analyzed the left ventricle transcriptome of 2.5- (Young), 12- (Middle age, MA) and 21- (Old) month-old female Rage-/- and C57BL/6 (WT) mice. By comparing Young, MA and Old Rage-/- versus age-matched WT mice, we identified 122, 192 and 11 differently expressed genes, respectively. Functional inference analysis showed that RAGE deletion is associated with: (i) a down-regulation of genes involved in antigen processing and presentation of exogenous antigen, adaptive immune response, cytokine and type I- and gamma-interferon mediated pathway in Young animals; (ii) an up-regulation of genes related to fatty acid oxidation, cardiac structure remodeling and impaired response to hypoxia in MA mice; (iii) an up-regulation of few genes belonging to complement activation and triglyceride biosynthetic process in Old animals. Our findings show that the age-dependent cardiac phenotype of Rage-/- mice is mainly associated to alterations of genes related to adaptive immunity and cardiac stress pathways.
2022-10-01 | GSE210192 | GEO
Project description:Cell surface heparan sulfate (HS) plays an essential role in RAGE signaling by inducing RAGE oligomerization. To understand the physiological significance of HS-induced RAGE oligomerization in vivo, we generated RAGE knock-in mice (RageAHA/AHA) by introducing point mutations to specifically disrupt HS–RAGE interaction. The RAGE variant expressed by RageAHA/AHA mice demonstrated normal ligand-binding but greatly impaired capacity of HS-binding and oligomerization. To grasp the full scale of the alteration in gene expression caused by knocking out Rage, we performed a RNAseq analysis of mature neutrophils and lung from WT, RageAHA/AHA and Rage-/- mice. The overall number of differently regulated genes (DEGs) in Rage-/- neutrophils were almost 2.5 times higher than in RageAHA/AHA neutrophils (603 vs. 247). In contrast, the number of DEGs were much less in lungs compared to neutrophils in both strains (202 DEGs in Rage-/- lungs and merely 31 DEGs in RageAHA/AHA lungs), however the difference between the two genotypes was even more dramatic in lungs (7-fold) than we observed in neutrophils (2.5-fold). By comparing transcriptomes of neutrophils and lung tissues from RageAHA/AHA and Rage-/- mice, we present clear evidence that complete deficiency of RAGE had much broader impact on global gene expression compared to point mutations of RAGE.
2021-05-11 | GSE174178 | GEO
Project description:The receptor for advanced glycation end products (RAGE) plays a key role in mammal physiology and in the etiology and progression of inflammatory and oxidative stress-based diseases. In adults, RAGE expression is high only in the lung where the protein concentrates in the basal membrane of Type I alveolar epithelial cells. In diseases, RAGE levels increase in the affected tissues and sustain chronic inflammation. RAGE exists as a single trans-membrane protein with an ectodomain and a short carboxyl-terminal tail essential for signaling, or also as a soluble ectodomain (sRAGE) that acts as a decoy receptor. The ectodomain is composed of a variable and two constant IgG-like domains (V, C1 and C2). VC1 is a single integrated unit responsible for binding of RAGE to the majority of its ligands including the advanced glycation End products (AGEs), S100 proteins and HMGB-1. Here, we report the identification of 20 new RAGE binding partners captured from human plasma and involved in the coagulation and complement processes and in the extracellular matrix. Four proteins contained a -carboxyl glutamic acid (Gla)-domain. Using MicroScale Thermophoresis, we quantified the interaction of prothrombin (PT) with VC1 and with sRAGE. Calcium competed in the binding of PT to sRAGE and PT devoid of the Gla-domain did not bind to sRAGE, providing evidence that the Gla-domain is critical for the interaction. Finally, the presence of VC1 delayed plasma clotting in a dose-dependent manner. We propose that RAGE is involved in modulating blood coagulation presumably in conditions of lung injury.
2020-07-14 | PXD020355 | Pride
Project description:The effect of resection of mouse livers on survival serve as a model for the effect of resection of human livers, which are performed for both the purposes of removing sick tissue and for transplanting healthy tissue. When less than 70% of a mouse liver is resected, the mouse usually lives. However, when more than 70% is resected, there is an increased probability that the mouse will die. We have found that deletion of Ager (Advanced Glycation End products receptor) (Rage) increases the chance of mouse survival relavtive to WT. Conversely, the deletion of Myd88 decreases the chances of survival, as does the simultaneous deletion of both Ager and Myd88. To understand these genotype/phenotype relations, we performed gene expression measurements. Gene expression of livers of WT C57BL/6 mice, Ager-null C57BL/6 mice, Myd88-null C57BL/6 mice, and Ager-null/Myd88-null C57BL/6 mice, all 10-12 weeks-old and sacrificed 2 hours after 85% liver resection, were compared. 4-6 replicates each group.
2012-06-25 | E-GEOD-22873 | biostudies-arrayexpress
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1µM, 5µM and negative control), with or without BMP2 (1µM).
2016-02-16 | GSE65952 | GEO