Yao Huan, Liang Caixia, Wang Xueting, Duan Chengwei, Song Xiao, Shang Yanxing, Zhang Mingyang, Peng Yiyun, Zhang Dongmei
Medical Research Center, Affiliated Hospital 2 of Nantong University, Nantong, 226001, China.
Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, China.
Neurosci Bull. 2025 May 24. doi: 10.1007/s12264-025-01418-z.
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.
小胶质细胞焦亡和神经炎症与脓毒症相关性脑病（SAE）的发病机制有关。OGT介导的O-连接N-乙酰葡糖胺化参与神经发育和损伤。然而，其在小胶质细胞焦亡中的调节功能以及在SAE中的作用仍不清楚。在本研究中，我们证明OGT缺陷会加剧小胶质细胞焦亡并加重继发性神经元损伤。此外，OGT抑制会损害健康小鼠的认知功能，并加速SAE小鼠的病情进展。机制上，OGT介导的ATF2第44位丝氨酸的O-连接N-乙酰葡糖胺化抑制其磷酸化和核转位，从而放大NLRP3炎性小体的激活，并促进小胶质细胞在LPS/尼日利亚菌素刺激下产生炎性细胞因子。总之，本研究揭示了OGT介导的O-连接N-乙酰葡糖胺化通过调节ATF2在调节小胶质细胞活性中的关键作用，从而预防SAE的进展。
