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

Traumatic brain injury (TBI) is a major global burden of health. As an accepted inflammatory mediator, high mobility group box 1 (HMGB1) is found to be effective in facilitating neurogenesis and axonal regeneration. SH3RF2 (also known as POSHER), an E3 ligase SH3 domain-containing ring finger 2, belongs to the SH3RF family of proteins. Here, we aimed to investigate the role of redox states of HMGB1 on neurite outgrowth and regeneration both . In this study, distinct recombinant HMGB1 redox isoforms were used. Sequencing for RNA-seq and data analysis were performed to find the potential downstream target of nonoxid-HMGB1 (3S-HMGB1). Protein changes and distribution of SH3RF2 were evaluated by western blot assays and immunofluorescence. Lentivirus and adeno-associated virus were used to regulate the expression of genes. Nonoxid-HMGB1-enriched exosomes were constructed and used to treat TBI rats. Neurological function was evaluated by OF test and NOR test. Results demonstrated that nonoxid-HMGB1 and fr-HMGB1, but not ds-HMGB1, promoted neurite outgrowth and axon elongation. RNA-seq and western blot assay indicated a significant increase of SH3RF2 in neurons after treated with nonoxid-HMGB1 or fr-HMGB1. Notably, the beneficial effects of nonoxid-HMGB1 were attenuated by downregulation of SH3RF2. Furthermore, nonoxid-HMGB1 ameliorated cognitive impairment in rats post-TBI SH3RF2. Altogether, our experimental results suggest that one of the promoting neurite outgrowth and regeneration mechanisms of nonoxid-HMGB1 is mediated through the upregulated expression of SH3RF2. Nonoxid-HMGB1 is an attractive therapeutic candidate for the treatment of TBI.