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A role for signalling via the molecule tumour necrosis factor in SAVI

Roger Brooks Senior Scientific Advisor

Article type:
Research

Estimated read time:
3 mins min read

Published:
11/11/2025

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Plain Language Summary This study explores how a protein called Tumour necrosis factor (TNF) affects immune responses in a genetic condition known as STING-associated vasculopathy with onset in infancy (SAVI), which causes severe inflammation and lung disease. By examining mice with changes in their genes, researchers found that TNF plays a significant role in worsening immune problems and tissue damage. The insights gained could help develop new treatments for SAVI and similar autoimmune diseases, aiming for better management and outcomes for affected patients.

Why it Matters Understanding the role of TNF signalling in SAVI provides insights into the mechanisms underlying severe autoimmune and inflammatory disorders. The study’s findings could lead to the development of targeted therapies that mitigate the effects of dysregulated immune responses, particularly in patients with STING-related conditions. Moreover, elucidating the interaction between TNF and STING pathways may offer broader implications for treating other inflammatory diseases and understanding the mechanisms of immune regulation.

Hope for the Future 

  1. Clinical Applications: The research opens avenues for developing therapies that specifically target TNF signalling pathways to treat SAVI and related inflammatory conditions more effectively.
  2. Further Research: Continued exploration of the TNF and STING interaction may reveal novel therapeutic strategies for a range of autoimmune diseases, promoting better patient outcomes.
  3. Precision Medicine: Insights from this study could enhance personalized medicine approaches by identifying specific biomarkers related to TNF signalling in patients with STING mutations.
  4. Understanding Other Conditions: The findings may have implications beyond SAVI, potentially informing treatment strategies for other disorders characterized by immune dysregulation.
  5. Innovative Therapies: Ongoing research may lead to the discovery of new drugs that inhibit harmful TNF signalling while preserving beneficial immune responses, thus improving therapeutic efficacy.

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Background The study investigates the role of TNF signalling in SAVI. SAVI is characterized by severe interstitial lung disease, T cell lymphopenia, skin inflammation, and dysregulated immune responses due to gain-of-function mutations in the STING gene. The research aims to clarify how TNF signalling influences the pathology associated with STING activation in a murine model of SAVI, particularly focusing on the impact of TNF receptors (TNFR1 and TNFR2) on immune cell behaviour and tissue responses.

What the Study Found: 

  1. TNF Signalling Role: TNF signalling is crucial for mediating the effects of STING activation on T cell maturation in the thymus and splenic pathology.
  2. T Cell Impact: Mice with genetically induced STING mutations exhibited significant T cell deficiencies, which were exacerbated by TNF signalling pathways.
  3. Neurodegeneration: The study found that STING-induced neurodegeneration was influenced by TNFR1 and TNFR2 signalling, suggesting that these receptors play a role in neuronal inflammation and degeneration.
  4. Inflammatory Pathways: The research demonstrated that inflammatory signalling pathways involving genes like CXCL10 and TNF were upregulated in STING mutant models, leading to functional impairments in immune responses.
  5. Endothelial Cell Function: The study highlighted the importance of STING expression in endothelial cells for leukocyte transmigration during inflammatory responses.
  6. Genetic Models: The investigation utilized STING knockout models to analyse the systemic effects of TNF signalling in the context of SAVI.
  7. Immune Dysregulation: Results indicated that TNF signalling contributes to the immune dysregulation observed in STING gain-of-function conditions, linking it to chronic inflammatory diseases.
  8. Therapeutic Insights: Findings suggest potential therapeutic targets within the TNF signalling pathway for managing symptoms associated with SAVI.

Citation Luksch et al., eLife 2025, 13, e101350

Authors Hella Luksch, Felix Schulze, David Geißler-Lösch, David Sprott, Lennart Höfs, Eva M Szegö, Wulf Tonnus, Stefan Winkler, Claudia Günther, Andreas