Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy (SAE). OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury. However, its regulatory function in microglial pyroptosis and involvement in SAE remains unclear. In this study, we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury. Furthermore, OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice. Mechanistically, OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation, thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation. In conclusion, this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.
Animals ; Microglia/metabolism* ; Pyroptosis/physiology* ; Mice ; Sepsis-Associated Encephalopathy/prevention & control* ; Activating Transcription Factor 2/metabolism* ; N-Acetylglucosaminyltransferases/genetics* ; Mice, Inbred C57BL ; Male ; Mice, Knockout

Objective To investigate the expression and relationship of early growth response gene-1((Egr-1)),platelet-derived growth factor-B(PDGF-B) and tranforming growth factor(TGF-?_1) in autogenous vein graft in rats,and the role in vein graft intimal hyperplasia(IH).Methods Autogenous vein graft model was(established) in 90 wistar rats.The vein graft samples were harvested at 1,2,6,24 hours,and 3,7,14,28,42 days after surgery.Normal vein was used as control group.Egr-1、PDGF-B,TGF-?_1 mRNA was measured by reverse transcription-PCR and in situ hybridization.Western blotting and immunohistochemistry were used to detect the protein expression of Egr-1,PDGF-B and TGF-?_1. Results Expression of Egr-1,PDGF-B,TGF-?_1 mRNA and protein was not detected in normal vein.In grafting vein,expression level of Egr1mRNA reached a peak at 28days,and the positive rate of Egr-1mRNA was 45%?6%;(PDGF-BmRNA) reached a peak at 14days(48%?6%);a peak of TGF-?_1mRNA was 46%?9% reached at 7days;Egr-1 protein expression reached a peak at 28days, and the positive rate of Egr-1 protein was 40%?9%.PDGF-B protein reached a peak at 28days(45%?4%),TGF-?_1 protein reached a peak at 14days(41%?7%).Conclusions Intimal hyperplasia of vein graft is closely associated withexpression of Egr-1、PDGF-B and TGF-?_1;the activation and expression of PDGF-B and TGF-?_1 may be(modulated) by Egr-1,and they may contribute to increase expression of Egr-1 by feedback.