Effector Memory T cells induce DC-intrinsic DNA damage and a non-canonical STING pathway during innate inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228682 | GEO | 2023/10/03
REPOSITORIES: GEO
Similar Datasets
Project description:A breach in tolerance to self-antigens induces expansion of autoreactive T cells, ultimately leading to autoimmune inflammation. While autoreactive T cells are principal drivers of autoimmunity, tissue pathology is alternatively driven by innate cytokines, indicating that autoreactive T cells can induce innate inflammation. This study has led to the discovery that effector memory T (Tem) cells trigger double stranded breaks via mitochondrial ROS production in interacting DCs. Consequently, initiation of the DNA damage response leads to activation of a cGAS-independent, STING-TRAF6-NFkB signaling axis. STING deficient DCs display significant defects in transcriptional induction and functional production of IL-1b and IL-6 following their interaction with Tem cells, both in vitro and in vivo. The discovery of Tem induced innate inflammation through DNA damage and a non-canonical STING-mediated NFkB activation presents this pathway as a potential target to alleviate T cell driven autoimmune inflammation.
2023-10-03 | GSE229204 | GEO
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: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:Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen presenting cells which function as critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia have been shown to upregulate CD11c during inflammation, making it challenging to distinguish hematopoietically-derived DCs from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells within the CNS during neuro-inflammation and is proposed as a mechanism for the regulation of innate cell function. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non-biased murine array. Several miRNAs, including miR-31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR-31 expression was specific to bone marrow-derived DCs (BMDCs). Interestingly, miR-31 binding sites were enriched in mRNAs downregulated BMDCs that migrated into the CNS. Finally, miR-31 was enriched in DCs that migrated through an in vitro blood-brain barrier. Our findings suggest that miRNAs, including miR-31, may participate in the regulation of DCs entry into the CNS during EAE and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS.
2019-01-31 | GSE111256 | GEO
Project description:Innate immune PRRs sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. Here we utilize a model of inflammation resulting from accrual of self DNA (DNase II-/- Ifnar-/-) to understand the role of PRR sensing pathways in arthritis and autoantibody production. Using mice deficient in DNase II/Ifnar together with deficiency in either STING or AIM2 (TKO), we reveal central roles for the STING and AIM2 pathway in arthritis. AIM2 TKO mice show limited inflammasome activation and, like STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, while DNase II-/- Ifnar-/- mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid sensing pathways in disease manifestations.
2014-12-25 | GSE63503 | GEO
Project description:Stimulator of interferon genes (STING), the central hub protein of the cGAS-STING signaling, is essential for type I IFN production of innate immunity. However, prolonged or excessive activation of STING is highly related to autoimmune diseases, most of which exhibit the hallmark of elevated expression of type I interferons and IFN-stimulated genes (ISGs). Thus, the activity of STING must be stringently controlled to maintain immune homeostasis. Here, we reported that CK1α, a protein serine/threonine kinase, was essential to prevent the over-activation of STING-mediated type I IFN signaling through autophagic degradation of STING. Mechanistically, CK1α interacted with STING upon the cGAS-STING pathway activation and promoted STING autophagic degradation by enhancing the phosphorylation of p62 at serine 349, which was critical for p62 mediated STING autophagic degradation. Consistently, SSTC3, a selective CK1α agonist, significantly attenuated the response of the cGAS-STING signaling by promoting STING autophagic degradation. Importantly, pharmaceutical activation of CK1α using SSTC3 markedly repressed the systemic autoinflammatory responses in the Trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CK1α in the autophagic degradation of STING to maintain immune homeostasis. Manipulating CK1α through SSTC3 might be a potential therapeutic strategy for alleviating STING-mediated aberrant type I IFNs in autoimmune diseases.
2024-01-31 | GSE226593 | GEO
Project description:Discovery of immune tolerance mechanisms, which inhibit pre-existing autoimmune inflammation, may provide us with new strategies for treating autoimmune diseases. We have identified a CD8αα+MHC-II+ cell with professional APC capacity during our investigation on spontaneous recovery from autoimmune glomerulonephritis in a rat model. This cell actively invades inflamed target tissue to terminate an on-going autoimmune inflammation by selective killing of effector autoreactive T cells. Now, we showed that this cell used a cytotoxic machinery of Ly49s+ NK cells in killing of target T cells. Thus, this CD8αα+MHC-II+ cell, which previously was thought a professional APC, is an antigen presenting-NK (AP-NK) cell. Following its coupling with target T cells through antigen presentation, killing stimulatory receptor Ly49s6 and co-receptor CD8αα on this cell used non-classic MHC-I RT1CE16 on the target T cells as a ligand to initiate killing. Thus, activated effector T cells with elevated expression of RT1CE16 were highly susceptible to the killing by the CD8αα+ AP-NK cell. Granule cytolytic perforin/granzyme C from this cell subsequently mediated cytotoxicity, and thus, inhibition of granzyme C effectively attenuated the killing. As it can recognize and eliminate effector autoreactive T cells in the inflamed target tissue, CD8αα+ AP-NK cell not only represents a new type of immune cell involved in immune tolerance, but also is a potential candidate for developing a cell-based therapy for pre-existing autoimmune diseases.
2016-09-20 | GSE87099 | GEO
Project description:The pathogenesis of rheumatoid arthritis (RA) is complicated and involves both innate and adaptive immunity [5]. The innate immunity such as macrophages or fibroblast-like synoviocytes (FLS) in the synovium can generate inflammatory mediators, including TNF-α, IL-1, IL-6, IL-17, IFN-γ, and chemo kines that lead to synovial inflammation, bone erosion, and cartilage damage [6-8]. The IL-17 signaling mediates the autoantibody production in collagen-induced arthritis (CIA) model [9]. However, the treatment response with an anti-IL17 monoclonal antibody in RA patients shows a high degree of heterogeneity [10]. The inhibitors of the Janus kinase (JAK) pathway are approved for RA patients [11]. These data suggest that the targeted multiple cytokines through the JAK pathway are useful for RA treatment. Disturbance of type I IFNs (IFNs-I) signaling and production drive autoimmune development [12]. The presymptomatic RA patients display an increase of IFNs-I before the onset of symptoms [13]. The RA patients also show the elevation of IFN- α in the synovial fluid and high expression of IFNs-I regulated gene in peripheral blood mononuclear cells (PBMC) [14]. However, the role of IFNs-I in arthritis and bone homeostasis has suggested the accelerating effect of arthritis and bone damage. The interferon-alpha receptor knockout mice develop arthritis severity higher than wild-type mice in the model of antigen-induced arthritis [15]. IFNs-I also affects the bone homeostasis by inhibiting osteoclastogenesis via receptor activator of nuclear factor-kappa B (RANK) pathway, and reduction of c-FOS expression [16-18]. Therefore, the goal of RA treatment with antagonizing the IFNs-I pathway has to be optimized between efficacy and potentially adverse effect. STING is a cytosolic DNA sensor that initiates the production of IFNs-I. STING functions have been reported as both pro-inflammatory signaling and negative regulator against inflammation [19-21]. The mutation in exon 5 of the STING gene results in gain function leading to initiate inflammation and cause the Sting associated vasculopathy with onset in infancy (SAVI) [22]. Loss of STING function rescues DNaseII-deficient mice from lethality and polyarthritis [23]. However, Sting-deficient lupus mice (MRL/Lpr mice) show higher and earlier mortality than Sting-sufficient MRL/Lpr mice [24]. The pathology also shows lymphoid hypertrophy with a higher amount of macrophages and granulocytes infiltration, autoantibodies, and cytokine [24]. The objective of this study was to identify the role of STING in the pathogenesis of rheumatoid arthritis using collagen-induced arthritis (CIA) model as a representative model of the human RA.
2020-06-26 | PXD018652 | Pride
Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional protein production. Purified ribosomes interact with and stimulate the catalytic activity of recombinant cGAS in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and causes the re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.
2021-09-09 | PXD019359 | Pride
Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional translation. Purified ribosomes interact with and stimulate recombinant cGAS catalytic activity in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and cause the re-localization of cGAS from the nucleus to the cytosol. Other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.
2020-05-26 | GSE151127 | GEO