Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
Summary
Macrophage mitochondrial complex III-derived superoxide is required for IL-10 secretion after TLR3/4 stimulation. Complex III-deficient mice are more susceptible to endotoxic shock, and PKA activation rescues IL-10 release, implicating an immunometabolic axis central to sepsis tolerance.
Key Findings
- Complex III-deficient macrophages secrete less IL-10 after TLR3/4 stimulation, and mice show increased susceptibility to IAV and LPS endotoxic shock.
- Restoring respiration with AOX without superoxide generation failed to rescue IL-10 release or shock susceptibility.
- PKA activation restored IL-10 secretion in complex III-deficient BMDMs; IL-4 responses were unaffected by complex III deficiency.
Clinical Implications
Although preclinical, targeting mitochondrial signaling or cAMP/PKA pathways to restore IL-10 could augment host tolerance in sepsis or endotoxemia.
Why It Matters
Reveals a previously unappreciated requirement for mitochondrial ROS in anti-inflammatory cytokine release and shock protection, opening avenues to modulate cAMP/PKA signaling in sepsis.
Limitations
- Mechanistic link between complex III superoxide and PKA signaling remains indirect
- Translational relevance to human sepsis not yet established; limited to murine and BMDM models
Future Directions
Define molecular intermediates linking complex III superoxide to cAMP/PKA and IL-10 transcription; test pharmacologic modulators in sepsis models and human macrophages.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study in murine models and primary cells
- Study Design
- OTHER