Prolonged loss of nuclear HMGB1 in neurons following modeled TBI and implications for long-term genetic health.

Abstract

Under normal physiological conditions high mobility group box protein 1 (HMGB1) stabilizes chromatin, controls transcription, and contributes to DNA repair. Cellular stress or injury results in HMGB1 release from the nucleus acting as a proinflammatory cytokine. The objective of this study was to characterize the temporal progression of nuclear HMGB1 loss up to one week following modeled TBI in 250 g male rats and correlate these changes with the response of DNA damage proteins. HMGB1 was present in the cytoplasm and absent from the nucleus of neurons within 6 h of injury. Quantitative immunohistochemistry and Western blot analysis showed a significant decrease in nuclear HMGB1 expression at 6 and 24 h post-injury compared to controls. Approximately 20 % of neurons were lacking nuclear HMGB1 expression at 7 days post-injury. Cells which were negative for nuclear HMGB1 expression labelled positive for HIF1α, PARP, and γH2AX, indicators of oxidative stress and DNA damage. Nuclear HIF1α expression was detected at 6 h after injury. Nuclear expression of HIF1α, PARP, and γH2AX was observed at 7 days post-injury, suggesting activation of oxidative stress response mechanisms and DNA damage repair pathways. The temporal changes in HMGB1 translocation in conjunction with expression of DNA damage markers suggest a relationship between injury-induced HMGB1 loss in neurons and subsequent DNA damage. These results highlight a potential injury response mechanism with long-term implications in relation to genetic health of surviving neurons.