Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling
- TU Dresden, Germany
- University Hospital Bonn, Germany
Abstract
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 order to investigate the role of signaling by tumor necrosis factor (TNF) in SAVI, we used genetic inactivation of TNF receptors 1 and 2 in murine SAVI, which is characterized by T cell lymphopenia, inflammatory lung disease and neurodegeneration. Genetic inactivation of TNFR1 and TNFR2, however, rescued the loss of thymocytes, reduced interstitial lung disease and neurodegeneration. Furthermore, genetic inactivation of TNFR1 and TNFR2 blunted transcription of cytokines, chemokines and adhesions proteins, which result from chronic STING activation in SAVI mice. In addition, increased transendothelial migration of neutrophils was ameliorated. Taken together, our results demonstrate a pivotal role of TNFR-signaling in the pathogenesis of SAVI in mice and suggest that available TNFR antagonists could ameliorate SAVI in patients.
Data availability
Transcriptomic data are deposited on GEO database, Accession no GSE244062.
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Tissue-specific inflammation induced by constitutively active STING is mediated by enhanced TNF signalingNCBI Gene Expression Omnibus, GSE244062.
Article and author information
Author details
David Geißler-Lösch
Andreas Linkermann
Björn H Falkenburger
Angela Rösen-Wolff
Funding
Deutsche Forschungsgemeinschaft (369799452-TRR237)
- Felix Schulze
Deutsche Forschungsgemeinschaft (EXC2151 - 390873048)
- Rayk Behrendt
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice experiments were approved by the Landesdirektion Sachsen (TVV 4/2019, TVV 13/2019) and carried out in accordance with the institutional guidelines on animal welfare.
Copyright
© 2025, Luksch et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling
eLife 14:e101350.
https://doi.org/10.7554/eLife.101350
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