TET2 Regulates the Neuroinflammatory Response in Microglia

Abstract

Graphical Abstract Highlights d TET2 is upregulated in microglia cells upon various inflammatory stimuli d TET2 regulates TLR-4-induced type I IFN response and LPSinduced aerobic glycolysis d TET2 regulates the proinflammatory response induced by LPS in vitro and in vivo d TET2 is expressed by amyloid b plaque-associated microglia in AD brains SUMMARY Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response.Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-kBdependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid b plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

“…BV2 cells are immortalized microglia cells that recapitulate a large proportion of the phenotypic traits of primary and in vivo microglia. They have been widely used to study microglia biology [ 42 , 43 , 44 ], and observations have successfully been validated in primary and in vivo microglia studies [ 104 , 105 , 106 ]. However, some limitations in the use of these cell lines have been reported.…”

Genome-wide association study of cognitive function in diverse Hispanics/Latinos: results from the Hispanic Community Health Study/Study of Latinos

“…Only two out of 148 previously identified loci met the criteria for replication in our study. These include a locus on chromosome 4q24, which encompasses TET2, a gene encoding a DNA demethylase with known roles in the microglial inflammatory response and neurodegenerative diseases; 77,78 and a locus on chromosome 13q31.2, which encompasses LINC00433 but no protein-coding gene. Taken together, these results further illustrate the need for larger samples of diverse Hispanics/Latinos and the potentially unique genetic architecture of cognitive function in this population.…”

Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

“…The downregulation of FOXP3 in LPS-stimulated microglial cells resulted in increased expression of HIF-1α, LDHA, as well as NO, CXCL10, and MCP-1, implicating the repressive effects of FOXP3 on microglial transition through metabolic regulation (Chung et al, 2010). Moreover, recent reports identified the epigenetic regulation of glycolytic genes hexokinase 3 (HK3) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) by ten eleven translocation enzyme 2 (TET2) in neurotoxic microglia (Carrillo-Jimenez et al, 2019). TET2 regulates the inflammatory responses in bone marrow-derived macrophages and dendritic cells (Zhang et al, 2015;Cull et al, 2017).…”

“…TET2 regulates the inflammatory responses in bone marrow-derived macrophages and dendritic cells (Zhang et al, 2015;Cull et al, 2017). Inflammatory stimulation of the microglial cells increased the expression of TET2, inducing neurotoxic activation of microglia (Carrillo-Jimenez et al, 2019). The TET2-mediated transition is controlled by glycolytic enzyme PFKFB3 (Carrillo-Jimenez et al, 2019).…”

“…Inflammatory stimulation of the microglial cells increased the expression of TET2, inducing neurotoxic activation of microglia (Carrillo-Jimenez et al, 2019). The TET2-mediated transition is controlled by glycolytic enzyme PFKFB3 (Carrillo-Jimenez et al, 2019).…”