206 Chapter 9 A D E F B C Figure 1. Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa TSPO expression in rodents but not humans (Adapted from Owen et al.,22). Human microglia show no increase in TSPO after proinflammatory stimulation (A). Human macrophages show a reduction in relative TSPO expression after proinflammatory stimulation (B,C). Contrastingly, mouse microglia and macrophages show a significant upregulation of TSPO after pro-inflammatory stimulation (p < 0.001, D,E). Radioligand binding of 3H-PBR28 decreases after proinflammatory stimulation of macrophages (F). This points towards a significant phylogenetic diversification of the regulation of the TSPO gene and perhaps a different role of the TSPO gene in humans versus rodents – possibly also related to the availability of the binding site of the PU.1 enhancer region in the TSPO gene which we found to be less accessible in humans compared to rodents in a pro-inflammatory environment. In summary, our studies, and the publicly available datasets on single cell expression of TSPO suggest a phylogenetic difference in the regulation of the TSPO gene. How, or why this diversification has taken place warrants more research into the function and role of the TSPO gene in inflammatory conditions. TSPO expression in humans does not increase when microglia adopt a pro-inflammatory state and thus TSPO PET signal reports on microglial density rather than phenotype. TSPO PET signal also is confounded by astrocytic TSPO expression under some conditions (e.g. inactive lesions in MS) and must thus be interpreted accordingly.
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