Nonoxid-HMGB1 Attenuates Cognitive Impairment After Traumatic Brain Injury in Rats

Area of Science:

• Neuroscience
• Cell Biology
• Regenerative Medicine

Background:

• Traumatic brain injury (TBI) presents a significant global health challenge.
• High mobility group box 1 (HMGB1) is an inflammatory mediator that aids neurogenesis and axonal regeneration.
• SH3RF2 (POSHER) is an E3 ligase involved in cellular processes.

Purpose of the Study:

• To investigate the role of high mobility group box 1 (HMGB1) redox states in neurite outgrowth and regeneration.
• To identify downstream targets of non-oxidized HMGB1 (3S-HMGB1) in neuronal regeneration.
• To explore the therapeutic potential of non-oxidized HMGB1 for TBI treatment.

Main Methods:

• Utilized distinct recombinant HMGB1 redox isoforms for in vitro and in vivo studies.
• Performed RNA-sequencing (RNA-seq) to identify downstream targets of non-oxidized HMGB1.
• Employed western blot, immunofluorescence, lentivirus, and adeno-associated virus for gene expression analysis and regulation.
• Constructed non-oxidized HMGB1-enriched exosomes for TBI rat treatment and assessed neurological function using OF and NOR tests.

Main Results:

• Non-oxidized HMGB1 and fragmentized HMGB1 (fr-HMGB1), but not disulfide HMGB1 (ds-HMGB1), promoted neurite outgrowth and axon elongation.
• RNA-seq and western blot revealed increased SH3RF2 expression in neurons treated with non-oxidized HMGB1 or fr-HMGB1.
• Downregulation of SH3RF2 attenuated the beneficial effects of non-oxidized HMGB1.
• Non-oxidized HMGB1 ameliorated cognitive impairment in TBI rats, mediated by SH3RF2.

Conclusions:

• Non-oxidized HMGB1 promotes neurite outgrowth and regeneration primarily through the upregulation of SH3RF2 expression.
• Non-oxidized HMGB1 demonstrates significant therapeutic potential for treating traumatic brain injury.
• The HMGB1-SH3RF2 pathway represents a promising target for TBI regenerative therapies.