Abstract
The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.
Highlights
The innate immune response is an emergent phenomenon arising from complex molecular and cellular signalling pathways
In the central nervous system (CNS), the innate immune response is orchestrated by microglial cells, capable of adopting differential functional states in response to stressors
Whilst translocator protein (TSPO) has been studied in a broad spectrum of disease states in positron emission tomography (PET) imaging studies, in this review we integrate more direct studies examining the role of TSPO in inflammatory responses, and its more central role in the modulation of mitochondrial energetic processes
Summary
The innate immune response is an emergent phenomenon arising from complex molecular and cellular signalling pathways. Cells 2020, 9, 512 and mediate apoptosis Facilitating these immune responses is mitochondrial reactive oxygen species (ROS) release and oxidative stress signalling [15–19], as well as the NLRP3 inflammasome complex activation [20]. It is, important to understand the subcellular drivers of microglial reactivity, which will aid in the detection and targeting of key mediators of these immune processes. Whilst TSPO has been studied in a broad spectrum of disease states in PET imaging studies, in this review we integrate more direct studies examining the role of TSPO in inflammatory responses, and its more central role in the modulation of mitochondrial energetic processes
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