TET2, an 'ambiguous' player in inflammation.

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Date: Aug. 2020
From: Neural Regeneration Research(Vol. 15, Issue 8)
Publisher: Medknow Publications and Media Pvt. Ltd.
Document Type: Article
Length: 2,161 words
Lexile Measure: 1540L

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Byline: Ana. Espinosa-Oliva, Miguel. Burguillos

Microglial cells, the 'macrophages' from the central nervous system (CNS), perform a variety of roles necessary to keep the homeostasis in the healthy brain. However, microglial cells are best known for their role as 'first responders' through initiation of an innate immune response against a wide variety of deleterious stimuli in the brain. This controlled inflammatory response is beneficial and disappears once the deleterious stimuli are gone. But, it is also well-acknowledged that uncontrolled activation may transform into a chronic neuroinflammatory response which is partially responsible for the progression of the disease, for instance in Parkinson's disease (PD) and Alzheimer's disease (AD) (Shen et al., 2018). For this reason, microglia have become a target in the search for new therapeutic strategies to hinder the progression of different neurodegenerative diseases, such as PD or AD.

Most cases of PD or AD are considered idiopathic, and the brain's environment (for instance, the presence of toxic aggregates of proteins) may modify the expression and/or activity of epigenetic modifying enzymes (Carrillo-Jimenez et al., 2019). These changes may affect the progression of such diseases by altering cellular signaling pathways, including the control of the neuroinflammatory response. Little is known about epigenetic modifying enzymes and their roles in microglial cells, although some studies have shown the importance of DNA methylation of cytosine guanine dinucleotides at promoters of cytokines such as interleukin (IL)-1ß in the neuroinflammatory response (Carrillo-Jimenez et al., 2019). DNA methylation is a stable and widespread epigenetic modification that allows inheritance of information in cells from one generation to the next. This epigenetic process is the result of a balance in the activity between DNA methyl transferase and Ten-eleven translocation (TET) enzymes. TETs are involved in the active and the passive demethylation process via oxidation of the methyl group of 5-methylcytosine to 5-hydroxymethylcytosine (Lio and Rao, 2019). In fact, 5-methylcytosine and 5-hydroxymethylcytosine are nowadays considered by many as the 5th and 6th base of DNA, respectively. Generally, the appearance of 5-hydroxymethylcytosine is strongly associated with active sites for gene transcription (Lio and Rao, 2019) and abnormal levels of TET activity (either via altered level of protein expression or mutations in the catalytic site) may promote changes in cell cycle that may lead to cell transformation. In fact, loss-of-function of TETs has been linked with the origin of several hematopoietic cancers of myeloid and lymphoid origin. Essentially, TET activity is considered to be key in the control of differentiation and development processes in myeloid and lymphoid cells, as well as a regulator of their immune functions (Lio and Rao, 2019).

Regarding the regulation of immune functions, TETs have been described as decisive players in various aspects of the inflammatory response driven by myeloid and lymphoid cells (Ichiyama et al., 2015; Zhang et al., 2015; Carrillo-Jimenez et al., 2019; Lio and Rao, 2019). These studies described that TETs can regulate the inflammatory response depending on or independently of its dioxygenase activity based on the nature of the inflammatory stimuli and type of...

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Gale Document Number: GALE|A613107729