Role of Sting in a lupus mouse model of Fcgr2b-deficient mice
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ABSTRACT:
PROVIDER: PRJNA597606 | ENA |
REPOSITORIES: ENA
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Project description:To determine the role of Sting pathway involving in the pathogenesis of SLE in a lupus mouse model of Fcgr2b-deficient mice. To identify mechanisms of the Sting signaling that contributes to SLE development
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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
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
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
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 DMBA or acetone treated wild type (WT) or STING deficient (SKO) mouse skin or skin tumor was examined for gene expression.
2014-05-31 | E-GEOD-57604 | biostudies-arrayexpress
Project description:BMDCs from WT, Fcgr2b-/- and Stinggt/gt were cultured, then stimulated with DMXAA for 3 and 6 hr. Cells were collected and lysed with 1 % IGEPAL CA-630, 0.5% TritonX-100, 150 mM NaCl, 50 mM Tris pH 7.4, 5% glycerol, 100 mM beta-Glycerophosphate, 2 mM Na3VO4 and 1X proteases inhibitor cocktail (Roche). First, antibody were mixed with the magnetic beads by adding 10 µg of STING antibody with 400 ug of SureBeads™ Protein A magnetic beads (Biorad, California, USA) and incubated for 1 hour at room temperature. Then, Protein lysates were added and incubated with antibody-conjugated beads for overnight at 4oC. After incubation, the beads were washed 3 times with wash buffer (150 mM NaCl and 50 mM Tris-HCL pH 7.4). Samples were eluted by adding 5X laemmli buffer and, boiled 950C for 10 minutes. The eluted protein samples were separated by 10 % SDS-PAGE gel. The STING interacting proteins from co-IP were analyzed by in-gel digestion followed by LC-MS/MS analysis.
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Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.
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