High mobility group box 1 orchestrates tissue regeneration via CXCR4

Area of Science:

• Cell Biology
• Molecular Biology
• Regenerative Medicine

Background:

• Tissue damage triggers inflammation and regeneration, but their coordination is poorly understood.
• High Mobility Group Box 1 (HMGB1) is a nuclear protein released upon injury, initiating inflammation.
• Different redox states of HMGB1 dictate its function: reduced HMGB1 is chemoattractant, while disulfide HMGB1 is proinflammatory.

Purpose of the Study:

• To investigate the role of HMGB1 redox states in coordinating inflammation and tissue regeneration.
• To determine the specific receptors involved in HMGB1-mediated tissue repair.
• To evaluate the therapeutic potential of HMGB1 variants for accelerating healing.

Main Methods:

• Utilized recombinant HMGB1 proteins (fully reduced, disulfide-bonded, and a non-oxidizable 3S mutant) in tissue injury models.
• Administered HMGB1 variants via injection to assess effects on muscle and liver regeneration.
• Analyzed cellular responses and receptor involvement (CXCR4, TLR4/MD-2, RAGE) using molecular and cellular assays.

Main Results:

• Fully reduced HMGB1 promotes muscle and liver regeneration by acting on resident stem cells, hepatocytes, and infiltrating cells.
• Regeneration mediated by reduced HMGB1 involves the CXCR4 receptor, independent of TLR4/MD-2 and RAGE.
• The non-oxidizable HMGB1 3S mutant accelerated regeneration more effectively than wild-type HMGB1 and without increasing inflammation.

Conclusions:

• The reduced form of HMGB1 is a key coordinator of tissue regeneration, primarily through CXCR4.
• Disulfide HMGB1 and its receptors TLR4/MD-2 and RAGE are not involved in this regenerative process.
• The HMGB1 3S mutant shows promise as a therapeutic agent for safely accelerating tissue repair and healing after injury.