Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling
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.
Authors
- Lino Lars Teichmann (ORCID: https://orcid.org/0000-0001-9489-7282)
- Andreas Linkermann (ORCID: https://orcid.org/0000-0001-6287-9725)
- Rayk Behrendt (ORCID: https://orcid.org/0000-0002-1091-2877)
- Claudia Günther (ORCID: https://orcid.org/0000-0002-4330-1861)
- Wulf Tonnus (ORCID: https://orcid.org/0000-0002-9728-1413)
- Angela Rösen‐Wolff (ORCID: https://orcid.org/0000-0002-9613-5879)
- Hella Luksch (ORCID: https://orcid.org/0000-0001-7070-4992)
- Éva M. Szegő (ORCID: https://orcid.org/0000-0002-2629-2131)
- Björn Falkenburger (ORCID: https://orcid.org/0000-0002-2387-526X)
- David Sprott
- Lennart Höfs (ORCID: https://orcid.org/0009-0009-3114-916X)
- Felix Schulze (ORCID: https://orcid.org/0000-0002-8220-5012)
- David Geißler-Lösch
- Stefan Winkler (ORCID: https://orcid.org/0000-0003-4020-4000)
Institutions
- University Hospital Bonn (DE)
- German Center for Neurodegenerative Diseases (DE)
- Center for Clinical Research (United States) (US)
- University Hospital Carl Gustav Carus (DE)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- eLife
- Published
- 2025-03-20
- DOI
- https://doi.org/10.7554/elife.101350
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Deutsche Forschungsgemeinschaft