Multi-omics analysis reveals GAPDH posttranscriptional regulation of IFN- γ and PHGDH as a metabolic checkpoint of microglia polarization

Brain Behav Immun. 2024 Jan 11;117:155-166. doi: 10.1016/j.bbi.2024.01.009. Online ahead of print.ABSTRACTA "switch" in the metabolic pattern of microglia is considered to be required to meet the metabolic demands of cell survival and functions. However, how metabolic switches regulate microglial function remains controversial. We found here that exposure to amyloid-β triggers microglial inflammation accompanied by increasing GAPDH levels. The increase of GAPDH, a glycolysis enzyme, leads to the reduced release of interferon-γ (IFN-γ) from inflammatory microglia. Such alternation is translational and is regulated by the binding of glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through influencing IFN-γ expression, regulates microglia functions, including phagocytosis and cytokine production. Phosphoglycerate dehydrogenase (PHGDH), screened from different state microglia by metabolomics combined with METARECON analysis, is a metabolic enzyme adjacent downstream of GAPDH and synthesizes serine on the collateral pathway derived from glycolysis. Polarization of microglial with PHGDH as a metabolic checkpoint can be bidirectionally regulated by adding IL-4 or giving PHGDH inhibitors. Therefore, regulation of metabolic enzymes not only reprograms metabolic patterns, but also manipulates microglia functions. Further study should be performed to explore the mechanism of metabolic checkpoints in huma...

Source: Brain, Behavior, and Immunity - January 12, 2024 Category: Neurology Authors: Shangchen Yang Ziqi Yuan Yufei Zhu Chensi Liang Zhenlei Chen Jie Zhang Lige Leng Source Type: research