Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Type I interferon responses to ischemic injury begin in the bone marrow of mice and humans and depend on Tet2, Nrf2, and Irf3

ABSTRACT: Sterile tissue injury is thought to locally activate innate immune responses via damage associated molecular patterns (DAMPs). Whether innate immune pathways are remotely activated remains relatively unexplored. Here, by analyzing ~145,000 single cell transcriptomes at steady state and after myocardial infarction (MI) in mice and humans, we show that the type I interferon (IFN) response, characterized by expression of interferon stimulated genes (ISGs), begins far from the site of injury, in neutrophil and monocyte progenitors within the bone marrow. In the peripheral blood of patients, we observed defined subsets of ISG-expressing neutrophils and monocytes. In the bone marrow and blood of mice, ISG expression was detected in neutrophils and monocytes and their progenitors; intensified with maturation at steady-state and after MI; and was dependent on Tet2 and Irf3 transcriptional regulators. Within the infarcted heart, ISG-expressing cells were negatively regulated by Nrf2-activation in Ccr2- steady-state cardiac macrophages. Our results show that IFN signaling begins in the bone marrow, implicate multiple transcription factors in its regulation (Tet2, Irf3, Nrf2), and provide a clinical biomarker (ISG score) for studying IFN signaling in patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE157244 | GEO | 2020/09/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

IRF3 and type I interferons fuel a fatal response to myocardial infarction [single cell RNA-Seq]

Project description:Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections1 and cancer2, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi?Goutières syndrome3,4 and STING-associated vasculopathy of infancy (SAVI)3. Myocardial infarction (MI) elicits inflammation5, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3?interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.

2017-11-06 | GSE106472 | GEO

IRF3 and type I interferons fuel a fatal response to myocardial infarction [bulk RNA-Seq]

2017-11-06 | GSE106471 | GEO

Primary human hepatocytes treated with IFNalpha and IL28B

Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with IFN, IL28b and T-PolyC after 6 or 24 hours respectively

2012-03-09 | E-GEOD-31264 | biostudies-arrayexpress

Transcription profiling by array of primary human hepatocytes derived from hepatitis C patients treated with type III interferons (IFNs) for 6 or 24 hours

Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with IFN or IL28b after 6 or 24 hours with three replications

2012-03-09 | E-GEOD-31193 | biostudies-arrayexpress

Primary human hepatocytes treated with IL28B and the HCV JFH1 Genotype 2A clone.

Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with JFHA, and IL28b respectively with three biological replication.

2013-08-16 | E-GEOD-31455 | biostudies-arrayexpress

HCMV-UV and SeV-UV infection of IFNAR KO and wildtype human fibroblasts

Project description:Type 1 interferon (IFN) plays a critical role in early antiviral defense and priming of adaptive immunity by signalling upregulation of host antiviral interferon-stimulated genes (ISGs). Certain stimuli trigger strong activation of IFN regulatory factor 3 (IRF3) and direct upregulation of ISGs in addition to IFN. It remains unclear why some stimuli are stronger activators of IRF3 and how this leads to IFN-independent antiviral protection. We found that UV-inactivated human cytomegalovirus (HCMV) particles triggered an IFN-independent ISG signature that was absent in cells infected with UV-inactivated Sendai virus (SeV) particles. HCMV particles triggered mostly uniform activation of IRF3 and low-level IFN-? production within the population while SeV particles triggered a small fraction of cells producing abundant IFN-?. These findings suggest that population level activation of IRF3 and antiviral protection emerges from a diversity of responses occurring simultaneously in single cells. Moreover, this occurs in the absence of virus replication.

2020-05-02 | GSE149705 | GEO

Two ISREs functioning cooperatively regulate ISG expression in West Nile virus infected IFNAR-/- MEFs

Project description:We previously identified a subset of interferon stimulated genes (ISGs), including Irf7, Irf1, Oas1a and Oas1b, upregulated by a West Nile virus (WNV) infection in wildtype mouse embryo fibroblasts (MEFs) after viral proteins had inhibited type 1 interferon (IFN)-mediated JAK-STAT signaling and also in WNV-infected STAT1-/-, STAT2-/-, IFNAR-/-, IRF3-/-, IRF7-/-, and IRF3/7-/- MEFs. In this study, ISG upregulation by WNV infection was inhibited in RIG-I/MDA5-/- but not in single knockout MEFs. ISGs upregulation was detected in WNV-infected IRF1-/- and IRF5-/- but was minimal in IRF3/5/7-/- MEFs, suggesting redundant IRF involvement. ISG upregulation by WNV infection in IFNAR-/- MEFs was confirmed by RNA-seq. We previously showed that a single proximal interferon stimulated response element (ISRE) in the Oas1a and Oas1b promoters bound the ISGF3 complex during IFN-dependent upregulation. In this study, we used wild-type and mutant promoter luciferase reporter constructs to identify critical regions in the Oas1b and Ifit1 promoters for IFN-independent transcriptional regulation. Two ISREs were required for both promoters. Mutation of these ISREs in an Ifit1 promoter DNA probe reduced in vitro complex formation. An NF-κB inhibitor decreased Ifit1 promoter activity in cells and in vitro complex formation. IRF3 and p50 binding was detected by ChIP for four upregulated ISGs with two proximal ISREs in their promoters. The data indicate that IFN-independent ISG expression of some ISGs is upregulated by two ISREs functioning cooperatively and the binding of a complex consisting of IRF3, 5, and/or 7 and an NF-κB component(s) as well as other as yet unknown factors.

2021-08-31 | GSE182446 | GEO

Sensors, Pathways and Transcription factors regulating IR-induced inflammatory transcriptional output [RNA-seq data set 1]

Project description:Bone marrow-derived macrophages derived from C57Bl/6, Myd88-/- and Trif-/-, Ifnar-/-, Atm-/-, Sting-/-, Scid, Irf3-/-, Irf1-/-, p53-/-, Nrf2-/-mice were irradiated with 6Gray ioninzing radiation; C57Bl/6 macrophages were Irradiated in the presence of MAPK inhibitors or Reactive Oxygen Species Scavenger (N-Acetyl Cysteine), Two biological replicates were generated for each time point. RNA samples were collected at 0 (unirradiated), 0.5, 1, 2, 6, and 24h post irradiation except where ever mentioned.

2017-10-01 | GSE100961 | GEO

RNA-seq reveals genes regulated by type I interferon during Rickettsia infection in WT and Irf-deficient bone marrow-derived macrophages

Project description:We report transcript abundance in murine bone marrow-derived macrophages (BMDMs) upon Rickettsia parkeri infection and treatment with type I interferon (IFN-I). Infections and IFN-I treatment were performed in parallel between WT BMDMs and BMDMs lacking genes encoding interferon-responsive factor (IRF) transcription factors, including IRF1, IRF5, and double mutant cells lacking both IRF3 and IRF7. Control cells were uninfected and not treated with IFN-I. The abundance of transcripts between these cells can be compared in order to identify genes specifically regulated by each IRF upon IFN-I treatment.

2019-07-04 | GSE128211 | GEO

Acute loss of TET function results in aggressive myeloid cancer in mice [WGBS]

Project description:To evaluate the DNA methylation in LSK cells from the bone marrow of wildtype or Tet2/3 DKO mice. In order to address the impact of the loss of Tet2/3 proteins in DNA methylation in LSK cells, we compared by WGBS the methylome of wild and, Tet2/3 DKO LSK cells in bone marrow.

2015-11-26 | E-GEOD-72629 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data