SIRT2 regulates HMGB1 nucleoplasmic shuttle and degradation via deacetylation in microglia by LPS

Abstract Background It is widely accepted that high mobility group box 1 (HMGB1) is a key inflammatory mediator in the pathogenesis of sepsis. HMGB1 promotes inflammation during sterile and infectious damage and plays a crucial role in disease development. Mobilization from the nucleus to the cytoplasm is the first important step in the release of HMGB1 from activated immune cells. Sirtuin 2 (SIRT2) is a member of the sirtuin family, nicotinamide adenine dinucleotide+-dependent deacylases, which participates in modulation of cell cycle control and neurodegeneration Methods A sepsis mouse modle was established using C57BL/6 and SIRT2-/- mice by LPS induction. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor IL-1β, IL-6, and HMGB1. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation. The impact of SIRT2 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT2. Results The results of our study showed that HMGB1 was reduced after SIRT2 knockdown. SIRT2 overexpression increased HMGB1. SIRT2 affected the translocation of HMGB1 from the nucleus to the cytoplasm. In addition, SIRT2 interacts with HMGB1 and deacetylates the K43 lysine sites. In vivo, a decrease in HMGB1 due to the absence of SIRT2. SIRT2 depletion increased HMGB1 ubiquitination and had an impact on the nucleoplasmic shuttle. Conclusion These discoveries are the first to shed light on the SIRT2 nucleoplasmic shuttle, which influences HMGB1 and its degradation, hence revealing novel therapeutic targets and avenues for sepsis treatment.