Methylglyoxal suppresses microglia inflammatory response through NRF2-IκBζ pathway
Shu-Li Wei,
Ying Yang,
Wei-Yue Si,
Yang Zhou,
Tao Li,
Tong Du,
Peng Zhang,
Xiao-Li Li,
Ruo-Nan Duan,
Rui-Sheng Duan,
Chun-Lin Yang
Affiliations
Shu-Li Wei
Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250011, PR China
Ying Yang
Department of Pharmacy, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
Wei-Yue Si
Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250011, PR China
Yang Zhou
Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China
Tao Li
Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China
Tong Du
Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China; Shandong Institute of Neuroimmunology, Jinan 250014, PR China
Peng Zhang
Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China; Shandong Institute of Neuroimmunology, Jinan 250014, PR China
Xiao-Li Li
Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China; Shandong Institute of Neuroimmunology, Jinan 250014, PR China
Ruo-Nan Duan
Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
Rui-Sheng Duan
Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250011, PR China; Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China; Shandong Institute of Neuroimmunology, Jinan 250014, PR China; Corresponding author. Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250011, PR China.
Chun-Lin Yang
Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China; Shandong Institute of Neuroimmunology, Jinan 250014, PR China; Corresponding author. Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, PR China.
Methylglyoxal (MGO) is a highly reactive metabolite generated by glycolysis. Although abnormal accumulation of MGO has been reported in several autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, the role of MGO in autoimmune diseases has not yet been fully investigated. In this study, we found that the intracellular MGO levels increased in activated immune cells, such as microglia and lymphocytes. Treatment with MGO inhibited inflammatory cell accumulation in the spinal cord and ameliorated the clinical symptoms in EAE mice. Further analysis indicated that MGO suppressed M1-polarization of microglia cells and diminished their inflammatory cytokine production. MGO also inhibited the ability of microglial cells to recruit and activate lymphocytes by decreasing chemokine secretion and expression of co-stimulatory molecules. Furthermore, MGO negatively regulated glycolysis by suppressing glucose transporter 1 expression. Mechanically, we found that MGO could activate nuclear factor erythroid 2-related factor 2 (NRF2) pathway and NRF2 could bind to the promoter of IκBζ gene and suppressed its transcription and subsequently pro-inflammatory cytokine production. In conclusion, our results showed that MGO acts as an immunosuppressive metabolite by activating the NRF2-IκBζ.
