TET2 Regulates the Neuroinflammatory Response in Microglia

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TET2 upregulation has been shown to improve neurogenesis and cognitive function in old mice. So it is interesting that researchers here link increased expression of TET2 with the inflammatory response of microglia in the brain. The broader context is that is becoming increasingly clear that dysfunctional and inflammatory microglia contribute significantly to the progression of neurodegenerative conditions. This is one of many examples of apparently contradictory results to illustrate the point that cellular biochemistry is very complex. Contradictions usually indicate that there is much left to be understood about the way in which the systems studied fit together in practice.

Microglia, the resident immune cells in the central nervous system, are key players in maintaining homeostasis in the brain. Microglia play a wide variety of roles under physiological and pathological conditions. In the healthy brain, microglia are responsible for neuronal activity-dependent synapse pruning during postnatal development. Upon neuronal injury or infection, microglia become rapid responders that initiate an innate inflammatory response. If the inflammatory response is exaggerated or chronic, it becomes detrimental for the surrounding neuronal population, as in Parkinson’s disease and Alzheimer’s disease.

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-κB-dependent 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 lipopolysaccharide. We observed that microglia associated with amyloid β plaques expressed TET2 in brain tissue from individuals with Alzheimer’s disease 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.

Link: https://doi.org/10.1016/j.celrep.2019.09.013

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