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STING inhibition ameliorates inflammation and fibrosis in preclinical models of peritoneal damage

ABSTRACT: STING inhibition ameliorates inflammation and fibrosis in preclinical models of peritoneal damage

PROVIDER: PRJNA1188589 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31415335.fastq.gz	Fastqsanger.gz
	SRR31415336.fastq.gz	Fastqsanger.gz
	SRR31415337.fastq.gz	Fastqsanger.gz
	SRR31415338.fastq.gz	Fastqsanger.gz
	SRR31415339.fastq.gz	Fastqsanger.gz

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STING inhibition ameliorates inflammation and fibrosis in preclinical models of peritoneal damage

Project description:Peritoneal dialysis (PD) is a widely used kidney replacement therapy for end-stage renal failure patients. However, long-term exposure to PD fluids (PDF) can lead to peritoneal membrane (PM) damage, causing ultrafiltration failure and thus PD. Investigating the molecular mechanisms underlying this damage is crucial for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients. In this work we study the role of the stimulator of interferon genes (STING), a key factor in recognising cytoplasmic DNA, in peritoneal inflammation and fibrosis. To this aim, we performed different preclinical mouse models of peritoneal inflammation, fibrosis, and adhesions. In a model of chlorhexidine gluconate (CHX)-induced inflammation significant changes in the peritoneal transcriptomic profile indicated that cytosolic DNA signaling was one of the most enriched KEGG pathways. In agreement with this finding, STING was upregulated in CHX- and PDF-exposed mice, and in peritoneal biopsies from PD patients. In early and advanced stages of the CHX models, STING genetic deficiency diminished peritoneal inflammation by preventing NF-κB pathway activation, downregulating inflammatory gene expression, and decreasing immune cell infiltration. STING absence also decreased PM thickness and fibrosis in the advanced CHX model, reduced adhesion scores in a post-surgical intra-abdominal adhesion model, and decreased inflammation in a S. epidermidis-induced peritonitis model. Furthermore, pharmacological inhibition of STING with C-176 decreased inflammation and macrophage-mediated mesothelial-to-mesenchymal transition in cultured mesothelial cells, and reduced CHX-induced PM thickness and inflammation in mice. Altogether, these findings highlight STING as a key mediator of peritoneal damage and suggest it may be a novel therapeutic target for preventing PD-associated peritoneal deterioration.

2024-11-25 | GSE282440 | GEO

Bacteroides thetaiotaomicron ameliorates colon inflammation in preclinical models of Crohn’s Disease

Project description:Bacteroides thetaiotaomicron ameliorates colon inflammation in preclinical models of Crohn’s Disease

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The effect of myeloid STING knockout on gene expression in colitic mice

Project description:Myeloid-derived STING has been recognized to play a vital role in mediating the development of colitis. We here report that myeloid-specific knockout of STING in adult mice ameliorates DSS-induced acute colitis through inhibiting macrophage maturation, reducing DC cell activation, and suppressing pro-inflammatory Th1 and Th17 cells.

2024-08-14 | GSE252100 | GEO

Bacteroides thetaiotaomicron ameliorates colon inflammation in preclinical models of Crohn’s Disease [Bacteroides]

Project description:Bacteroides thetaiotaomicron ameliorates colon inflammation in preclinical models of Crohn’s Disease [Bacteroides]

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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

Inflammation-Driven Carcinogenesis is Mediated through STING [skin]

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

Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis.

Project description:Peritoneal fibrosis is a major complication in peritoneal dialysis (PD) patients, which leads to dialysis discontinuation. Periostin, increased by transforming growth factor ?1 (TGF-?1) stimulation, induces the expression of extracellular matrix (ECM) genes. Aberrant periostin expression has been demonstrated to be associated with PD-related peritoneal fibrosis. Therefore, the effect of periostin inhibition by an aptamer-based inhibitor on peritoneal fibrosis was evaluated. In vitro, TGF-?1 treatment upregulated periostin, fibronectin, ?-smooth muscle actin (?-SMA), and Snail expression and reduced E-cadherin expression in human peritoneal mesothelial cells (HPMCs). Periostin small interfering RNA (siRNA) treatment ameliorated the TGF-?1-induced periostin, fibronectin, ?-SMA, and Snail expression and restored E-cadherin expression in HPMCs. Similarly, the periostin-binding DNA aptamer (PA) also attenuated fibronectin, ?-SMA, and Snail upregulation and E-cadherin downregulation in TGF-?1-stimulated HPMCs. In mice treated with PD solution for 4 weeks, the expression of periostin, fibronectin, ?-SMA, and Snail was significantly increased in the peritoneum, whereas E-cadherin expression was significantly decreased. The thickness of the submesothelial layer and the intensity of Masson's trichrome staining in the PD group were significantly increased compared to the untreated group. These changes were significantly abrogated by the intraperitoneal administration of PA. These findings suggest that PA can be a potential therapeutic strategy for peritoneal fibrosis in PD patients.

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Bacteroides thetaiotaomicron ameliorates colon inflammation in preclinical models of Crohn’s Disease [mouse colon]

Project description:Bacteroides thetaiotaomicron ameliorates colon inflammation in preclinical models of Crohn’s Disease [mouse colon]

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Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner II

Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact. Peritoneal macrophages from mutant and control mice were isolated by FACS. Total RNA was subjected to next generation mRNA sequencing.

2022-10-10 | GSE214712 | GEO

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner I

2022-10-10 | GSE214711 | GEO