Endothelial STING and STAT1 mediate IFN-independent effects of IL-6 in an endotoxemia-induced model of shock.
Summary
IL-6 elicits a transient, IFN-independent IFN-like gene program in endothelial cells via STAT1–cGAS–STING and IRFs, uncoupled from STAT3-mediated barrier regulation. Endothelial STING or global STAT1 deficiency attenuates endotoxemia responses and suppresses IFN-like signatures in vivo, revealing parallel IL-6 downstream pathways.
Key Findings
- IL-6 induces a transient IFN-like gene program in human endothelial cells via a noncanonical, IFN-independent mechanism.
- This program requires STAT1, cGAS, STING, and IRF1/3/4 but is independent of STAT3.
- Endothelial STING knockout or global STAT1 knockout mice show attenuated responses to endotoxemia and lack the endotoxin-induced IFN-like signature.
- SOCS3 loss in endothelium enhances IFN-like responses in kidneys and brains during endotoxemia.
Clinical Implications
Targeting endothelial DNA-sensing components (e.g., STING) or STAT1 may modulate IL-6–driven vascular inflammation in shock and sepsis, potentially complementing IL-6 or JAK pathway inhibitors.
Why It Matters
This study uncovers a noncanonical IL-6–STAT1–cGAS–STING axis in endothelium that drives IFN-like transcriptional responses in shock, redefining IL-6 signaling complexity and suggesting new intervention points.
Limitations
- Endotoxemia models may not capture the complexity of human polymicrobial sepsis.
- Therapeutic targeting feasibility and safety of endothelial STING/STAT1 modulation remain to be tested.
Future Directions
Evaluate endothelial-targeted STING/STAT1 modulators in polymicrobial sepsis models and assess synergy with IL-6/JAK pathway inhibitors.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Mechanistic preclinical study using knockout mice and primary human endothelial cells.
- Study Design
- OTHER