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, 37 (8), 2679-2690

Pro-inflammatory Activation of Primary Microglia and Macrophages Increases 18 kDa Translocator Protein Expression in Rodents but Not Humans

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Pro-inflammatory Activation of Primary Microglia and Macrophages Increases 18 kDa Translocator Protein Expression in Rodents but Not Humans

David R Owen et al. J Cereb Blood Flow Metab.

Abstract

The 18kDa Translocator Protein (TSPO) is the most commonly used tissue-specific marker of inflammation in positron emission tomography (PET) studies. It is expressed in myeloid cells such as microglia and macrophages, and in rodent myeloid cells expression increases with cellular activation. We assessed the effect of myeloid cell activation on TSPO gene expression in both primary human and rodent microglia and macrophages in vitro, and also measured TSPO radioligand binding with 3H-PBR28 in primary human macrophages. As observed previously, we found that TSPO expression increases (∼9-fold) in rodent-derived macrophages and microglia upon pro-inflammatory stimulation. However, TSPO expression does not increase with classical pro-inflammatory activation in primary human microglia (fold change 0.85 [95% CI 0.58-1.12], p = 0.47). In contrast, pro-inflammatory activation of human monocyte-derived macrophages is associated with a reduction of both TSPO gene expression (fold change 0.60 [95% CI 0.45-0.74], p = 0.02) and TSPO binding site abundance (fold change 0.61 [95% CI 0.49-0.73], p < 0.0001). These findings have important implications for understanding the biology of TSPO in activated macrophages and microglia in humans. They are also clinically relevant for the interpretation of PET studies using TSPO targeting radioligands, as they suggest changes in TSPO expression may reflect microglial and macrophage density rather than activation phenotype.

Keywords: Positron emission tomography; inflammation; macrophages; microglia; neurodegeneration.

Figures

Figure 1.
Figure 1.
Changes in TSPO gene expression of unstimulated foetal microglia (FM, n = 8) and human adult microglia (HAM, n = 18) relative to expression in monocyte derived macrophages (MDM, n = 15) (ANOVA, p < 0.0002).
Figure 2.
Figure 2.
Relative changes in TSPO gene expression in independent cohorts of human microglia. Stimulated conditions are referenced relative to unstimulated conditions. (a) Human adult microglia (n = 18, ANOVA, p = 0.47). (b) Foetal microglia (n = 8, ANOVA, p = 0.51).
Figure 3.
Figure 3.
(a) Changes in TSPO gene expression of human monocyte-derived macrophages (MDM) under stimulated conditions relative to unstimulated conditions (n = 15, ANOVA, p = 0.02). (b) Plot comparing individual MDM TSPO gene expression responses to pro-inflammatory stimulatory conditions (n = 15, paired t test p < 0.0001).
Figure 4.
Figure 4.
Changes in TSPO gene expression of rodent myeloid cells under pro-inflammatory conditions relative to unstimulated conditions. (a) Mouse microglia (n = 5, paired t test p < 0.0007). (b) Mouse macrophages (n = 3, paired t test p < 0.0009).
Figure 5.
Figure 5.
Effect of stimulatory conditions in human monocyte derived macrophages (MDM) on 3H-PBR28 radioligand binding parameters Bmax and Kd. (Kd, n = 3, F test, p = 0.65. Bmax, n = 3, F test, p ≤ 0.0001). For each condition, the plot represents the mean of three independent donors. Each concentration was assayed in triplicate for each donor.

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