Differential gene regulation downstream of murine Tmem173 variants
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE68140 | GEO | 2016/01/03
SECONDARY ACCESSION(S): PRJNA281931
REPOSITORIES: GEO
Similar Datasets
Project description:We report positional cloning and characterization of a novel Sting allele that fails to activate IFN production in the wild-derived mice of MOLF/Ei strain in response to HSV (Herpes Simplex Virus) and Listeria monocytogenes both in vitro and in vivo. We show that previously uncharacterized mutations in the N-terminal of STING are responsible for low levels of IFN due to failure of MOLF STING to respond to cytosolic STING agonists such as 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) or poly(deoxyadenylic-deoxythymidylic) acid (dAdT). Using Next-Generation Sequencing (NGS) for the analysis of DNA-responses in congenic C57BL6.StingMOLF/MOLF (MOLF STING) mouse macrophages, we show that these mutations in MOLF/Ei discriminate in responses between different STING agonists. Macrophages from C57BL6.StingB6/B6¬ (B6 STING), or B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. To examine differential gene regulation downstream of murine Tmem173 (STING) allelic variants. We stimulated macrophages from B6 mice congenic for MOLF STING; macrophages from B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. One replicate of RNA-seq reads after each stimulation provided. Conditions are peritoneal macrophages from B6 congenic mice expressing: B6 STING, MOLF STING, or STING KO stimulated with 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), poly(deoxyadenylic-deoxythymidylic) acid (dAdT), or no treatment. This constitutes a total of 12 reads analyzed in this data set.
2016-07-05 | E-GEOD-68140 | biostudies-arrayexpress
Project description:Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive T cell immunity.
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Project description:Vascular disrupting agents (VDA) represent a novel approach to the treatment of cancer, resulting in collapse of tumor vasculature and tumor death. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced Phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. The data presented herein demonstrate that DMXAA is a novel and specific activator of the TBK1-IRF-3 signaling pathway. DMXAA treatment of primary murine macrophages resulted in robust IRF-3 activation, a ~750-fold increase in IFN-beta mRNA and, in contrast to the potent Toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal NF-kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3, but MyD88-, TRIF-, IPS-1/MAVS-, and IKKbeta-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of murine macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid (SA). These findings detail a novel pathway for TBK-1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs. Experiment Overall Design: Microarray analysis was carried out using Affymetrix® mouse array 430A_2 exposed to total RNA prepared from C57BL/6J or IFN-beta-/- macrophages that had been treated with medium alone or DMXAA for 3 h. Fold-induction was calculated using Affymetrix® GeneChip® Operating Software. A >3-fold increase or decrease between inducible and basal mRNA levels was set as the criteria for inclusion of a gene as modulated.
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Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
2024-01-22 | GSE253724 | GEO
Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
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Project description:Vascular disrupting agents (VDA) represent a novel approach to the treatment of cancer, resulting in collapse of tumor vasculature and tumor death. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced Phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. The data presented herein demonstrate that DMXAA is a novel and specific activator of the TBK1-IRF-3 signaling pathway. DMXAA treatment of primary murine macrophages resulted in robust IRF-3 activation, a ~750-fold increase in IFN-beta mRNA and, in contrast to the potent Toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal NF-kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3, but MyD88-, TRIF-, IPS-1/MAVS-, and IKKbeta-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of murine macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid (SA). These findings detail a novel pathway for TBK-1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs. Keywords: DMXAA, IRF-3, TBK1, IFN-beta, Salicylic acid, TLR
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