The Role And Mechanism Of SIRT1-mediated Deacetylation Of The HMGB1/NF-?B Pathway On Modulating Microglia Polarization And Neuroinflammatory Responses Following Experimental Traumatic Brain Injury

Background Traumatic brain injury(TBI)is an acute and deadly emergency of the central nervous system with high morbidity and mortality.Microglial polarization and the subsequent neuroinflammatory response are contributing factors for TBI induced secondary injury.Extracellular secreted high mobile group box 1(HMGB1)is considered to be the central component of the late inflammatory response.By binding to its specific receptor RAGE or toll-like receptor,HMGB1 can activate NF-?B and other inflammatory pathways and then induce neuroinflammatory response.Activation of the HMGB1/NF-?B pathway is closely related to HMGB1 protein lysine residues acetylation,which is regulated by the sirtuin family(SIRTs).However,the mechanism of the acetylation of HMGB1 on modulating microglia polarization and neuroinflammatory responses following experimental traumatic brain injury is unclear.Hence,this study aimed at comprehensively elaborating the significance of HMGB1/NF-?B pathway on modulating microglia polarization and neuroinflanmmatory responses after TBI both clinically and basically.Methods The levels of HMGB1 were analyzed by using ELISA assay in the serum of patients with TBI and their clinical significance were also investigated.The Feeney DM TBI model was adopted to induce brain injury in rats.The expressions and cell distributions of HMGB1 at different time points after TBI were analyzed by using western blotting and immunofluorescent double staining.HMGB1 inhibition experiments were used to explore the effect of HMGBI/NF-kB pathway on microglial M1/M2 subtype polarization and neuroinflammatory response after TBI.Finally,immunoprecipitation and western blotting were used to detect the effects of SIRTI on HMGBI nucleoplasmic metastasis,extracellular secretion and the activation of HMGB1/NF-?B pathway after TBI.Results The results of our clinical study showed that the serum levels of HMDB1 in patients were elevated significantly in the early period of TBI,which were closely related to the disease severity of TBI.The expressions of HMGBI were increased in the rat lesioned cortices after TBI,and mainly expressed in neuron and microglia.The inhibition of HMGB1/NF-?B pathway promoted a shift from the M1 microglial phenotype to the M2 microglial phenotype and inhibited microglial activation,thus reducing TBI-induced inflammatory factors,and thereby improve the neurological function after TBI.The activity of HMGBI/NF-?B pathway was a lysine acetylation dependent mechanism.Up-regulated expression and activity of SIRTI induced HMGBI deacetylation and direct interactions between SIRT1 and HMGB1 following TBI.These events lead to inhibition of HMGB1 nucleocytoplasmic translocation,extracellular secretion,and alleviated HMGBI-mediated activation of the NF-?B pathway following TBI-induced microglial activation,thus sequestering the subsequent inflammatory response.Conclusion The results of our clinical and basic studies suggest that SIRT1 attenuates the neuroinflammatory response by modulating microglial polarization through mediating lysine residues deacetylation of the HXMGB 1/NF-?B pathway,leading to neuroprotective effects afterTBI.