HMGB1 is a mediator of cuproptosis-related sterile inflammation

Area of Science:

• Cell Biology
• Immunology
• Molecular Medicine

Background:

• Cuproptosis is a novel cell death pathway induced by copper-dependent mitochondrial stress.
• The inflammatory mediators released during cuproptosis remain largely unknown.
• Understanding these mediators is crucial for addressing sterile inflammation associated with this cell death modality.

Purpose of the Study:

• To identify the key mediators responsible for initiating sterile inflammation following cuproptosis.
• To elucidate the molecular mechanisms by which these mediators are released.
• To investigate the role of these mediators in downstream inflammatory signaling.

Main Methods:

• Investigated the release of damage-associated molecular patterns (DAMPs) from cuproptotic cells.
• Utilized RNA interference (RNAi) and pharmacologic inhibitors (dorsomorphin) to modulate AMP-activated protein kinase (AMPK) activity.
• Assessed inflammatory cytokine production in response to HMGB1 and its receptor (AGER/RAGE).

Main Results:

• High-mobility group box 1 (HMGB1) is released by cuproptotic cells, acting as a DAMP to initiate inflammation.
• Copper accumulation induces adenosine triphosphate (ATP) depletion, activating AMPK, which promotes HMGB1 phosphorylation and release.
• Inhibition of AMPK significantly reduces both cuproptosis and HMGB1 release.
• HMGB1-deficient cells show diminished induction of inflammatory cytokines via the AGER/RAGE pathway.

Conclusions:

• HMGB1 is a critical immune mediator released during cuproptosis.
• AMPK activation is essential for HMGB1 release in response to copper-induced mitochondrial stress.
• HMGB1 plays a key role in driving sterile inflammation initiated by cuproptosis through the AGER/RAGE pathway.