TSPO regulation in reactive gliotic diseases

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In the past decade, there has been an increase in both our interest and understanding of the regulation of brain metabolism (Choi et al., 2012; Harris, Jolivet, & Attwell, 2012; Kasischke et al., 2004; Magistretti, 2007). Of particular interest are the mechanisms by which glial cells control metabolic processes (Lee et al., 2014; Pascual et al., 2012; Pinacho et al., 2016). Consequently, dysregulation in energy metabolism in diseased states has also become a field of great interest (Ewers et al., 2014; Haight et al., 2013; Lama et al., 2014; Mehta et al., 2013). Regardless of the type of tissue or cell type in the body, the mitochondria are the chief regulator of cellular metabolism and adenosine triphosphate (ATP). Therefore, mitochondrial dysfunction is central to the pathogenesis and cellular damage associated with stroke and other debilitating neuroinflammatory disorders. The aforementioned diseases have now become grouped as a common set of pathologies relating to mitochondria (Alcocer‐Gómez et al., 2014; Baxter et al., 2014; Hauser & Hastings, 2013). Following impaired mitochondrial function, oxidative stress develops from an increase in reactive oxygen species (ROS; Rada et al., 2011). Cytokine secretion further initiates changes in glial cells ranging from morphology changes to proliferation (Eder, 2005; Selmaj et al., 1990). The consequences of these changes disrupt the tight metabolic coupling between neurons and glia (Kasischke et al., 2004; Magistretti & Allaman, 2015; Magistretti, 2007). This coupling is highly regulated to efficiently control energy metabolism, but when dysregulated leads to disease (Magistretti & Allaman, 2015; Zhang et al., 2014). The coupling of cytokine release with an increase in neuronal energy demand signals glial cells to become reactive (Araque, Carmignoto, & Haydon, 2001; Vázquez‐Chona et al., 2011).This cumulative process in glial cells is referred to as reactive gliosis (Sofroniew, 2005; Burda & Sofroniew, 2014). The reactive gliotic process is not a binary process but instead represents a continuum. However, if reactive gliosis continues for longer periods of time it becomes unregulated and dysfunctional. This temporal change in reactive gliosis marks the difference between chronic and acute pathogenesis. Further chronic reactive gliosis results in a marked upregulation of many signaling factors relating to neuroinflammation (Balasingam et al., 1994). Central to these inflammatory cascades are pathways that are involved in sensing cellular stress (Mancuso et al., 2007).
One protein implicated as a sensor of cellular stress is the 18kDa translocator protein (TSPO). TSPO resides on the outer mitochondrial membrane (OMM) and although formerly known as the peripheral benzodiazepine receptor, it is enriched in the CNS particularly in glial cells with microglia bearing higher expressing than other types (Cosenza‐Nashat et al., 2009). TSPO has been implicated in a multitude of metabolic processes, and of particular interest, TSPO is known to become highly enriched in diseased brains during the process of neurodegeneration (Gulyás et al., 2011). Although recently debated (Papadopoulos et al., 2017), the most well known role for TSPO is in the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate limiting step in the production of neurosteroids (Figure 1; Papadopoulos et al., 1997; Vallée et al., 2001). After being transported into the mitochondria, cholesterol is converted to pregnenolone and then trafficked to the cytoplasm where it can be converted to a number of neurosteroids. The recent debate in the area of TSPO's role in cholesterol transport stems from studies that have used genetic manipulations in mice to deplete TSPO, which failed to produce a deficit in steroid production (Morohaku et al., 2014; Tu et al., 2014; Tu et al., 2015).
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