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Intrinsic self-DNA triggers inflammatory disease dependent on STING (I)

ABSTRACT: Inflammatory diseases such as Aicardi-Goutieres Syndrome (AGS) and severe systemic lupus erythematosus (SLE) are generally lethal disorders that have been traced to defects in the exonuclease Trex1 (DNAseIII). Mice lacking Trex1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the STING (stimulator of interferon genes) pathway. Here we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into Trex1-/- mice. Trex1-/- macrophages did not exhibit significant augmented ability to produce pro-inflammatory cytokines compared to normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE59217 | GEO | 2014/07/09

SECONDARY ACCESSION(S): PRJNA254749

REPOSITORIES: GEO

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Intrinsic self-DNA triggers inflammatory disease dependent on STING (I)

Project description:Inflammatory diseases such as Aicardi-Goutieres Syndrome (AGS) and severe systemic lupus erythematosus (SLE) are generally lethal disorders that have been traced to defects in the exonuclease Trex1 (DNAseIII). Mice lacking Trex1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the STING (stimulator of interferon genes) pathway. Here we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into Trex1-/- mice. Trex1-/- macrophages did not exhibit significant augmented ability to produce pro-inflammatory cytokines compared to normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies. Total RNA obtained from wild type (WT), Trex1 deficient (TKO), STING deficient (SKO), or Trex1 and STING double deficient (STKO) mouse Heart

2014-07-09 | E-GEOD-59217 | biostudies-arrayexpress

Intrinsic self-DNA triggers inflammatory disease dependent on STING (II)

Project description:Inflammatory diseases such as Aicardi-Goutieres Syndrome (AGS) and severe systemic lupus erythematosus (SLE) are generally lethal disorders that have been traced to defects in the exonuclease Trex1 (DNAseIII). Mice lacking Trex1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the STING (stimulator of interferon genes) pathway. Here we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into Trex1-/- mice. Trex1-/- macrophages did not exhibit significant augmented ability to produce pro-inflammatory cytokines compared to normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies. Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), Trex1 deficient MEFs (TKO) or STING and Trex1 double deficient MEFs (STKO) transfected with or without double strand DNA 90 (ISD) and examined cytokine production by these cells.

2014-07-09 | E-GEOD-59218 | biostudies-arrayexpress

Intrinsic self-DNA triggers inflammatory disease dependent on STING (II)

2014-07-09 | GSE59218 | GEO

Inflammation-Driven Carcinogenesis is Mediated through STING [MEFs]

Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), STING deficient MEFs (SKO), Trex1 deficient MEFs (TKO), and both STING and Trex1 deficient MEFs (STKO) treated with DMBA and examined cytokine production by these cells.

2014-05-31 | E-GEOD-57603 | biostudies-arrayexpress

Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity

Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3â repair exonuclease (Trex)1 cause Aicardi-GoutiÃ¨res syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency. We sorted CD19-positive B cells from spleens of Trex1fl/fl CD19-Cre+ and Trex1fl/fl CD19-Cre- mice and isolated total RNA for library construction to perform mRNA deep sequencing.

2016-08-01 | E-GEOD-77693 | biostudies-arrayexpress

TREX1 is required for microglial cholesterol homeostasis and subsequent oligodendrocyte maturation during brain development [bulk RNA-seq]

Project description:Three Prime Repair Exonuclease 1 (TREX1) gene mutations have been associated with Aicardi-Goutières Syndrome (AGS) – a rare, severe pediatric autoimmune disorder that primarily affects the brain and has a poorly understood etiology. Microglia are brain-resident macrophages indispensable for brain development and implicated in multiple neuroinflammatory diseases. However, the role of TREX1 – a DNase that cleaves cytosolic nucleic acids, preventing viral- and autoimmune-related inflammatory responses – in microglia biology remains to be elucidated. Here, we leverage a model of human embryonic stem cell (hESC)-derived engineered microglia-like cells, bulk and single-cell transcriptomics, optical and transmission electron microscopy, and three-month-old assembloids composed of microglia and regionalized neural organoids to interrogate TREX1 functions in human microglia. Our analyses suggest that TREX1 influences cholesterol metabolism, leading to an active microglial morphology with increased phagocytosis in the absence of TREX1. Notably, regulating cholesterol metabolism with an HMG-CoA reductase inhibitor, FDA-approved atorvastatin, rescues these microglial phenotypes. Functionally, TREX1-deficient microglia selectively affect oligodendrocyte maturation and myelination in assembloids. Together, these results suggest routes for therapeutic intervention in pathologies such as AGS based on microglia-specific molecular and cellular mechanisms.

2023-11-23 | GSE216702 | GEO

Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity

Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3’ repair exonuclease (Trex)1 cause Aicardi-Goutières syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency.

2016-08-01 | GSE77693 | GEO

Identification of gene expression patterns in spleen of TREX1-mutated mice

Project description:Investigating gene expression patterns in mice with conditional expression of the most common RVCL mutation, V235fs, and another mice expressing a conditional C-terminal mutation, D272fs, associated with a case of human SLE. Mutations at the N-terminus affecting TREX1 DNase activity are associated with autoimmune and inflammatory conditions such as Aicardi-Goutières syndrome (AGS). Mutations in the C-terminus of TREX1 cause loss of localization to the ER and dysregulation of oligosacchryltransferase (OST) activity, and are associated with retinal vasculopathy with cerebral leukodystrophy (RVCL) and in some cases with systemic lupus erythematosus (SLE).

2018-03-15 | GSE96687 | GEO

Time-dependent alteration of gene expression after induced knockout of Trex1 in bone marrow derived macrophages.

Project description:Defects in three prime repair exonuclease (TREX1) cause the type I interferonopathy Aicardi Goutières syndrome. In absence of TREX1 some unknown DNA is accumulating in the cytosol which triggers cGAS/STING activation and type I interferon production. This analysis was designed to understand the kinetics of accumulation of the pathogenic cGAS ligand and the resulting altered gene expression upon induced loss of TREX1.

2022-04-01 | GSE197291 | GEO

Reverse transcriptase inhibitors in Aicardi-Goutières syndrome

Project description:Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous encephalopathy whose pathology is linked to an abnormal type I interferon response induced by self-derived nucleic acids. Data indicate that endogenous retroelements represent one source of interferon-stimulatory self-nucleic acid. No effective therapies are available for this disorder. In this pilot study involving patients with AGS due to mutations in TREX1, RNASEH2A, RNASEH2B or SAMHD1 three nucleoside analogue reverse transcriptase inhibitors (RTIs) were administered over 12 months. Transcription profiling was done by RNA-seq.

2018-12-12 | E-MTAB-7087 | biostudies-arrayexpress

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