STAT1 and IRF8 orchestrate IFNγ and LPS-mediated signal integration in the vasculature that leads to amplified pro-atherogenic responses
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE49519 | GEO | 2014/11/04
SECONDARY ACCESSION(S): PRJNA214100
REPOSITORIES: GEO
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Project description:Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by vascular inflammation and lipid-laden plaque formation within the intima of the vessel wall. Atherosclerosis is initiated by recruitment of blood leukocytes to the injured vascular endothelium and leads to altered contractility of Vascular Smooth Muscle Cells (VSMCs), acute and chronic luminal obstruction, abnormalities of blood flow and diminished oxygen supply to target organs. The pro-inflammatory pathways activated by Toll-like Receptors (TLRs), and Interferons (IFNs) have been identified as key components of atherogenesis. These pathways culminate in the activation of Signal Transducers and Activator of Transcription (STAT)1-containing complexes ISGF3 and GAF, and Nuclear factor-κB (NFκB) that coordinate expression of multiple chemokines, adhesion molecules, antiviral and antimicrobial proteins in vascular and immune cells. IFN-I and IFN-II participate in signaling cross-talk with TLR4 through combinatorial actions of ISGF3 and GAF with NF-kB leading to enhanced gene expression. Currently it is not clear how this signal integration is regulated at the genome-wide level and if similar mechanisms are activated by the different IFNs in vascular cells as compared to macrophages and dendritic cells. Therefore, we compared genome-wide transcriptional responses of mouse VSMCs, macrophages (BMDMs) and dendritic cells (DCs) in response to IFNα, IFNγ or LPS alone, or after combined treatment using RNA-seq. Consequently, commonly up-regulated genes in VSMCs, BMDMs and DCs could be identified after combined treatment with IFNα+LPS, as well as after combined treatment with IFNγ+LPS. Generally, in all three cell-types combined treatment with IFNα+LPS or IFNγ+LPS resulted in a synergistic increase in gene expression as compared to single treatments. Also, significant functional overlap could be observed between commonly upregulated genes in response to IFNα+LPS and IFNγ+LPS. Using ChIP-seq on chromatin from VSMCs, STAT1 and p65 bound IFNα+LPS and IFNγ+LPS up-regulated genes were identified, containing GAF/GAS, ISGF3/ISRE or NF-kB binding motifs located in promoter regions, but also to up- and downstream genomic regions. Comparing IFNα+LPS and IFNγ+LPS commonly upregulated genes identified a substantial overlap of ISRE-containing genes. Interestingly, STAT1 as part of ISGF3 was shown to bind the promoter of these ISRE-containing genes in response to IFNα as well as IFNγ. Moreover, different binding modes of STAT1-p65 co-binding were detected, including GAS-NFκB, ISRE-NFκB or GAS-ISRE-NFκB, shared by IFNα+LPS and IFNγ+LPS up-regulated genes. This cooperative involvement involved a STAT1-dependent role in the nearby recruitment of p65 already upon single IFNα or IFNγ treatment, via closely located GAS-NFĸB or ISRE-NFĸB binding sites in promoter regions. More important, this STAT1-p65 co-binding was significantly increased upon subsequent LPS exposure and resulted in amplified transcriptional activity of IFNα+LPS and IFNγ+LPS upregulated genes.
2019-06-04 | GSE120807 | GEO
Project description:Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by vascular inflammation and lipid-laden plaque formation within the intima of the vessel wall. Atherosclerosis is initiated by recruitment of blood leukocytes to the injured vascular endothelium and leads to altered contractility of Vascular Smooth Muscle Cells (VSMCs), acute and chronic luminal obstruction, abnormalities of blood flow and diminished oxygen supply to target organs. The pro-inflammatory pathways activated by Toll-like Receptors (TLRs), and Interferons (IFNs) have been identified as key components of atherogenesis. These pathways culminate in the activation of Signal Transducers and Activator of Transcription (STAT)1-containing complexes ISGF3 and GAF, and Nuclear factor-κB (NFκB) that coordinate expression of multiple chemokines, adhesion molecules, antiviral and antimicrobial proteins in vascular and immune cells. IFN-I and IFN-II participate in signaling cross-talk with TLR4 through combinatorial actions of ISGF3 and GAF with NF-kB leading to enhanced gene expression. Currently it is not clear how this signal integration is regulated at the genome-wide level and if similar mechanisms are activated by the different IFNs in vascular cells as compared to macrophages and dendritic cells. Therefore, we compared genome-wide transcriptional responses of mouse VSMCs, macrophages (BMDMs) and dendritic cells (DCs) in response to IFNα, IFNγ or LPS alone, or after combined treatment using RNA-seq. Consequently, commonly up-regulated genes in VSMCs, BMDMs and DCs could be identified after combined treatment with IFNα+LPS, as well as after combined treatment with IFNγ+LPS. Generally, in all three cell-types combined treatment with IFNα+LPS or IFNγ+LPS resulted in a synergistic increase in gene expression as compared to single treatments. Also, significant functional overlap could be observed between commonly upregulated genes in response to IFNα+LPS and IFNγ+LPS. Using ChIP-seq on chromatin from VSMCs, STAT1 and p65 bound IFNα+LPS and IFNγ+LPS up-regulated genes were identified, containing GAF/GAS, ISGF3/ISRE or NF-kB binding motifs located in promoter regions, but also to up- and downstream genomic regions. Comparing IFNα+LPS and IFNγ+LPS commonly upregulated genes identified a substantial overlap of ISRE-containing genes. Interestingly, STAT1 as part of ISGF3 was shown to bind the promoter of these ISRE-containing genes in response to IFNα as well as IFNγ. Moreover, different binding modes of STAT1-p65 co-binding were detected, including GAS-NFκB, ISRE-NFκB or GAS-ISRE-NFκB, shared by IFNα+LPS and IFNγ+LPS up-regulated genes. This cooperative involvement involved a STAT1-dependent role in the nearby recruitment of p65 already upon single IFNα or IFNγ treatment, via closely located GAS-NFĸB or ISRE-NFĸB binding sites in promoter regions. More important, this STAT1-p65 co-binding was significantly increased upon subsequent LPS exposure and resulted in amplified transcriptional activity of IFNα+LPS and IFNγ+LPS upregulated genes.
2019-06-04 | GSE120806 | GEO
Project description:Interferon (IFN)γ and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFNγ–priming and subsequent TLR4 activation induces so called classically activated macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4–treated macrophages, commonly called alternatively activated, are known to develop enhanced capacity for endocytosis, antigen presentation, and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4–dependent global gene activation program in IFNγ– versus IL-4–pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4– versus IFNγ–primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in alternatively primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNγ priming was actually found to suppress LPS–induced gene expression in a Stat1–dependent manner. Our data suggest that IL-4–priming is not per se anti-inflammatory but generates a macrophage that is “tissue protective” but still capable of mounting a strong inflammatory response after TLR4–dependent activation. Keywords: Gene expression profiling Gene expression was investigated in mouse bone marrow-derived macrophages (BMM). On day 7, BMM were stimulated with either IL-4 or IFNγ overnight (18h in total). LPS treatment was performed in primed and unprimed macrophages 4 h prior to harvesting. At least three independent experiments were performed for each condition.
2010-10-01 | E-GEOD-21895 | biostudies-arrayexpress
Project description:Rateitschak2012 - Interferon-gamma (IFNγ) induced STAT1 signalling (PC_IFNg100)
This model is described in the article:
Parameter identifiability and sensitivity analysis predict targets for enhancement of STAT1 activity in pancreatic cancer and stellate cells.
Rateitschak K, Winter F, Lange F, Jaster R, Wolkenhauer O.
PLoS Comput. Biol. 2012; 8(12): e1002815
Abstract:
The present work exemplifies how parameter identifiability analysis can be used to gain insights into differences in experimental systems and how uncertainty in parameter estimates can be handled. The case study, presented here, investigates interferon-gamma (IFNγ) induced STAT1 signalling in two cell types that play a key role in pancreatic cancer development: pancreatic stellate and cancer cells. IFNγ inhibits the growth for both types of cells and may be prototypic of agents that simultaneously hit cancer and stroma cells. We combined time-course experiments with mathematical modelling to focus on the common situation in which variations between profiles of experimental time series, from different cell types, are observed. To understand how biochemical reactions are causing the observed variations, we performed a parameter identifiability analysis. We successfully identified reactions that differ in pancreatic stellate cells and cancer cells, by comparing confidence intervals of parameter value estimates and the variability of model trajectories. Our analysis shows that useful information can also be obtained from nonidentifiable parameters. For the prediction of potential therapeutic targets we studied the consequences of uncertainty in the values of identifiable and nonidentifiable parameters. Interestingly, the sensitivity of model variables is robust against parameter variations and against differences between IFNγ induced STAT1 signalling in pancreatic stellate and cancer cells. This provides the basis for a prediction of therapeutic targets that are valid for both cell types.
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2015-03-14 | BIOMD0000000585 | BioModels
Project description:Analysis of differentially expressed genes (DEGs) revealed a striking upregulation of interferon genes in P301S, compared to non-transgenic hippocampi, and enrichment of transcription factor motifs of interferon-response factors (IRFs) and interferon-sensitive response elements (ISREs). Cgas deletion reduced the induction of a subset of tau-stimulated inflammatory and cytokine expression including interferon stimulated genes such as Stat1, Ddx60, Isg20, Rnf213, Parp12, Ifi35, and Sp100. Thus, microglial cGAS promotes IFN-I expression in response to tau.
2023-04-26 | GSE226380 | GEO
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Project description:Gene expression profiling for mouse N1 and N2 neutrophils. Neutrphils were isolated form the bone marrow of C57BL/6J mice between 12-16 weeks old. Approximately 8x10^7 neutrophils were used per condition and were split into 3 biological replicates. Freshly isolated neutrophils were cultured for 2h in RPMI medium, in the presence of 100 ng/ml lipopolysaccharide (LPS) and 20 ng/ml interferon gamma (IFNγ) or 20 ng/ml interleukin 4 (IL-4). Total RNA was isolated with TRIzol reagent and Phasemaker tubes. A sample from the LPS+IFNγ polarization did not pass the quality control test and was excluded from the downstream analysis.
2021-07-29 | E-MTAB-10508 | biostudies-arrayexpress
Project description:Targeting tumor-infiltrating Treg cells is an efficient way to evoke an anti-tumor immune response. How Treg cells fragility and stability are regulated remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. Conversely, the decreased IFITM3 protein and mRNA levels present in STAT1-deficient Treg cells indicate that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of TI-Tregs in the tumor model. Overall, our study demonstrates that the perturbation of TI-Tregs through IFNγ-IFITM3-STAT1 feedback is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.
2023-11-21 | GSE248223 | GEO
Project description:Cardiovascular diseases (CVD), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis and plaque development include the pro-infslammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of members of the Signal Transducer and Activator of Transcription (STAT) family. Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT-specific. We hypothesized that non-specific STAT-inhibitors that simultaneously block STAT1, STAT2 and STAT3 activity and pro-inflammatory target gene expression may be a promising avenue for the treatment of CVD. We developed a pipeline approach combining comparative in silico docking of multiple STAT-SH2 models on multi-million Clean Lead and Clean Drug-Like libraries with in vitro STAT inhibition validation, as a novel STAT-inhibitory selection strategy. This approach allowed us to identify a new type of non-specific STAT inhibitor, C01L_F03 targeting the SH2 domain of STAT1, 2 and 3 with equal affinity. Moreover we observed a similar STAT cross-binding mechanism for STATTIC and STX-0119, leading to genome-wide inhibition of pro-atherogenic gene expression. Consequently, a multi-STAT inhibitory strategy was applied to inhibit endothelial cell (EC) migration, leukocyte adhesion to ECs and impairment of aortic ring contractility under inflammatory conditions. Together, this implicates that multi-STAT inhibition could provide a powerfull approach for the success of combating vascular inflammation in CVD
2017-07-18 | GSE101508 | GEO
Project description:We have identified a number of miRNAs that are differentially expressed in LPS and IFNγ treated RAW264.7 cells, as compared to untreated cells. Microarray and quantitative real-time PCR (qRT-PCR) results showed that miR-103 decreased while the STAT1 expression increased substantially in RAW264.7 derived M1 macrophage, and there was a significant negative correlation between miR-103 and STAT1.Overexpression of miR-103 suppressed M1 polarization by inhibiting STAT1/IRF1 signaling pathway and vice versa in vitro. STAT1 is a direct target of of miR-103.
2020-10-28 | GSE143845 | GEO