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Series GSE244062 Query DataSets for GSE244062
Status Public on Apr 16, 2024
Title Tissue-specific inflammation induced by constitutively active STING is mediated by enhanced TNF signaling
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI) in humans and in mice. Murine SAVI is characterized by T cell lymphopenia, severe inflammatory interstitial lung disease, neuroinflammation and neurodegeneration with only limited contribution of type I interferon signaling. Here, we show that pharmacologic inhibition of TNF signaling in SAVI mice improved T cell lymphopenia, but had no effect on interstitial lung disease. However, complete blocking of TNF receptor signaling by knocking out TNFR1 and TNFR2 in SAVI mice rescued both, loss of thymocytes as well as interstitial lung disease. Furthermore, chronic STING signaling in lung endothelial cells of diseased mice enhanced transcription of cytokines, chemokines and adhesions proteins resulting in increased transendothelial migration of neutrophils across the endothelial barrier that could be reverted by genetic inactivation of TNFR1 and 2. Thus, our results demonstrate a pivotal role of TNFR-signaling in the development of SAVI-associated lung disease and suggest this pathway as promising target to ameliorate human SAVI
Overall design Murine lung endothelial cells were isolated from perfused (10 U/ml heparin diluted in PBS) lung tissue. Single cell suspension was obtained after digestion with 1 mg/ml Collagenase (Sigma-Aldrich), 3.5 mg/ml Dispase (Roche) and 25 µg/ml DNaseI (Roche) in native IMDM (Thermo fisher scientific) over 45 min at 37°C. Collected cells were washed with PBS and passed through a 30 µm cell strainer. Lung endothelial cells were enriched by positive selection of CD31+ cells with microbeads (Miltenyi Biotec), according to the manufacturer’s protocol. All selected cells were stained with antibodies (all from BioLegend) against CD45.2 (1:300), CD11b (1:500), Ter-119 (1:500), CD326 (1:500), CD31 (1:300) and separated by FACS Aria. Dead cells and cellular debris were excluded by PI staining.
Contributor(s) Behrendt R, Luksch H, Rösen-Wolff A
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Submission date Sep 26, 2023
Last update date Apr 16, 2024
Contact name Rayk Behrendt
Phone +4922828751120
Organization name Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Department Nucleic Acid Immunity & Genome Defense
Lab The 3ehrendt Lab
Street address Venusberg-Campus 1
City Bonn
State/province North Rhine-Westphalia
ZIP/Postal code 53127
Country Germany
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (16)
GSM7805963 WT CTRL 1
GSM7805964 WT CTRL 2
GSM7805965 WT CTRL 3
BioProject PRJNA1021178

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Supplementary file Size Download File type/resource
GSE244062_bfx1909.counts.tsv.gz 4.4 Mb (ftp)(http) TSV
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Raw data are available in SRA

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