TET2 regulates the neuroinflammatory response in microglia

Abstract:

Summary Epigenetic mechanisms regulate distinct aspects of the inflammatory response in various immune cell types. Despite the central role for microglia, the resident macrophages of the brain, in neuroinflammation and neurodegeneration little is known about their epigenetic 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-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes that lead to early metabolic alterations, as well as a later inflammatory response independently of its 5mC oxidation activity at the affected genes. We further show that TET2 regulates the proinflammatory response in microglia induced by intraperitoneal injection of LPS in vivo . We observed that microglia associated to amyloid β plaques, recently defined as disease-associated microglia, expressed TET2 in brain tissue from individuals with Alzheimer’s disease (AD) and in 5×FAD 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.