Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases I

Microglial activation plays central roles in neuro-inflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state. Human monocyte derived macrophages (MDMs) were obtained from fresh blood of male and female healthy donors (n = 6) between 20 and 60 years after CD14-affinity purification. Cells were then treated with or without LPS (100ng/ml) for 24 hours. Total RNA was collected by rRNA depletion before generating cDNA libraries. Illumina sequencing was used to obtain a minimum of 40 million paired-end reads per sample.