David R Owen Division of Brain Sciences, Imperial College London, UK Positron emission tomography (PET) with radiotracers which bind the 18kDa Translocator Protein (TSPO) is commonly used to quantify microglial activation in humans in vivo. The rationale for TSPO PET is based on the assumption that TSPO expression is low in homeostatic microglia, but is rapidly and substantially induced as these cells become activated by pro-inflammatory stimuli. Indeed, in primary rodent microglia, stimulation with LPS induces 7-10 fold increases in TSPO expression within hours. However, when we directly tested this in primary human microglia, there was no change in TSPO gene or protein expression upon proinflammatory stimulation in microglia isolated from: 1) temporal lobe biopsies (n=18), 2) post mortem samples (n=7), and 3) human foetal microglia (n=8). Furthermore, in primary human monocyte derived macrophages, TSPO gene and protein expression decreased upon cellular activation (fold change 0.60, 95% CI 0.45-0.74). These data imply that changes in TSPO PET signal may reflect microglial number rather than activation state.
We have also revealed that a polymorphism in human TSPO, not present in rodents, causes a substantial reduction (up to 50 fold) in binding affinity of almost all TSPO radiotracers. This also has implications for study design and signal interpretation as subjects with the same TSPO expression will have different PET signal if they are of different TSPO genotype.
Future work improving our understanding of how TSPO expression is associated with immune phenotype in microglia, but also other cell types including astrocytes and endothelial cells, is needed to ensure that this potentially powerful tool is used most effectively
Funding Medical Research Council Clinical Scientist Fellowship MR/N008219/1
Credits: None available.
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