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The cGAS/STING pathway suppresses TLR-dependent systemic autoimmunity in TMPD-mediated SLE

ABSTRACT: The purpose of the study was to identify differentially regulated genes between WT MRL/Lpr strain and cGAS deficeint MRL/Lpr strain. We utilized Nanostring technology to analze RNA obtained from spleen of these mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE169655 | GEO | 2021/03/26

REPOSITORIES: GEO

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The cGAS/STING pathway suppresses TLR-dependent systemic autoimmunity in TMPD-mediated SLE

Project description:The cGAS/STING pathway suppresses TLR-dependent systemic autoimmunity in TMPD-mediated SLE

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cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE.

Project description:Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASKOFaslpr mice on a pure MRL/Faslpr background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.

| S-EPMC8040952 | biostudies-literature

Diagnosis and early detection of CNS-SLE in MRL/lpr mice using peptide microarrays (GPL14921)

Project description:We investigated whether mouse serum autoantibody binding patterns on random-sequence peptide microarrays (immunosignaturing) can be used for diagnosing and predicting the onset of lupus and its central nervous system (CNS) manifestations. Submitter states "We have no processed data to submit. We have no gpr files to submit." To identify possible predictive and diagnostic peptides of lupus and CNS-lupus, we carried out two studies and selected peptides in common across both studies. In the first study we tested 3-6 MRL/lpr, MRL/mp and C3H/HeJ mice at four months of age. For study two we tested 9-10 MRL/lpr and MRL/mp at 1.5 and 4 months of age. In both studies the mice sera were diluted 1/500 and analyzed using microarray peptides from platform GPL14921. We ran each sample in triplicate. The MRL/lpr and MRL/mp are the autoimmune strains and the C3H/HeJ is the control strain.

2014-05-08 | E-GEOD-57388 | biostudies-arrayexpress

Lung samples from SLE model mice with or without mouse-adapted SARS-CoV-2 infection

Project description:Lung samples were generated from female mice of MRL/MpJ-+/+(MpJ) and MRL/MpJ-lpr/lpr (lpr) on 3 days post infection of mouse-adapted SARS-CoV-2 or non-infected condition.

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CK1α suppresses autoimmunity by restraining the cGAS-STING signaling

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.

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MATRIN3 deficiency leads to cGAS-STING activation (NanoString)

Project description:MATRIN3 deficiency leads to cGAS-STING activation (NanoString)

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Remodeling of Mouse Hippocampus Genomic Fabrics in Neuropsychiatric Systemic Lupus Erythematosus

Project description:TNF-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the hippocampi of MRL/+, MRL/lpr and MRL/lpr-Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on hippocampal gene expression in lupus. We found that the TWEAK/Fn14 pathway strongly affects the expression level, variability and coordination of the genomic fabrics responsible for neurotransmission and chemokine signaling. Dysregulation of the PI3K-Akt pathway in the MRL/lpr lupus strain compared with the MRL/+ control and Fn14ko mice was particularly prominent and therefore promising as a potential therapeutic target, although the complexity of the transcriptomic fabric highlights important considerations in in vivo experimental models.

2021-03-24 | GSE169486 | GEO

Remodeling of Neurotransmission and Chemokine Signaling Genomic Fabrics in Neuropsychiatric Systemic Lupus Erythematosus

Project description:Cognitive dysfunction and mood changes are prevalent and especially taxing issues to patients with systemic lupus erythematosus (SLE). TNF-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/lpr and MRL/lpr-Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on cortical gene expression in lupus. We found that the TWEAK/Fn14 pathway strongly affects the expression level, variability and coordination of the genomic fabrics responsible for neurotransmission and chemokine signaling. Dysregulation of the PI3K-Akt pathway in the MRL/lpr lupus strain compared with the MRL/+ control and Fn14ko mice was particularly prominent and therefore promising as a potential therapeutic target, although the complexity of the transcriptomic fabric highlights important considerations in in vivo experimental models.

2021-01-03 | GSE164140 | GEO

CK1α suppresses autoimmunity by restraining the cGAS-STING signaling

Project description:CK1α suppresses autoimmunity by restraining the cGAS-STING signaling

| PRJNA940749 | ENA

Evaluation of microRNA levels in recipient BMMSCs of MRL/lpr mice after cell therapy (miRNA)

Project description:Mesenchymal stem cell transplantation (MSCT) has been widely used to treat a variety of human diseases. However, the detailed mechanisms underlying its success are not fully understood. Here we show that MSCT rescues recipient bone marrow mesenchymal stem cell (BMMSC) function in Fas-deficient-MRL/lpr systemic lupus erythematosus (SLE) mice via a miR-29b/Dnmt1/Notch epigenetic cascade. Using the microRNA microarray, we found that MSCT could rescue the high level of miR-29b in the recipient BMMSCs of MRL/lpr mice. In the present study, mesenchymal stem cell transplantation (MSCT) was used to treat MRL/lpr mice. One week after the treatment, normal control MSCs from C3H/HeJ mice (C3H), recipient MSCs from untreated MRL/lpr mice (LPR) and recipient MSCs from MSCT-treated MRL/lpr mice (MSC) were used for total RNA extraction and microRNA microarray for analysis of microRNA expressions.

2014-03-20 | E-GEOD-55971 | biostudies-arrayexpress

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