OGT-Mediated O-GlcNAcylation of ATF2 Protects Against Sepsis-Associated Encephalopathy by Inhibiting Microglial Pyroptosis
Huan Yao1,2 · Caixia Liang1 · Xueting Wang1,3 · Chengwei Duan1 · Xiao Song4 · Yanxing Shang1 · Mingyang Zhang1,2 · Yiyun Peng1,2 · Dongmei Zhang1,2
1 Medical Research Center, Afliated Hospital 2 of Nantong University, Nantong 226001, China
2 Department of Pathogen Biology, Medical College, Nantong University, Nantong 226001, China
3 Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
4 Department of Emergency, Afliated Hospital 2 of Nantong University, Nantong 226001, China
Abstract
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.
Keywords
O-GlcNAc transferase (OGT); Activation transcription factor 2 (ATF2); Microglia; Pyroptosis; Sepsis-associated encephalopathy (SAE)
