Cited by 194Neuroinflammation and Neurodegeneration MechanismsPharmacological Receptor Mechanisms and EffectsMedical Imaging Techniques and Applications

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Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans

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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 3 H-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.

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Crossref · 10.1177/0271678x17710182

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Figures

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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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.
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.CC BY · PubMed Central

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Metadata

Authors
Owen, D. R., Narayan, N., Wells, L., Healy, L., Smyth, E., Rabiner, E. A., Galloway, D., Williams, J. B., Lehr, J., Mandhair, H., Peferoen, L. A., Taylor, P. C., Amor, S., Antel, J. P., Matthews, P. M., & Moore, C. S.
Affiliations
  • Hammersmith Hospital (GB)
  • University of Oxford (GB)
  • Montreal Neurological Institute and Hospital (CA)
  • King's College London (GB)
  • Memorial University of Newfoundland (CA)
  • Vrije Universiteit Amsterdam (NL)
  • Queen Mary University of London (GB)
Corresponding author
Owen, David R
Venue
Journal of Cerebral Blood Flow & Metabolism
Published
2017-05-22
Volume
37
Issue
8
Pages
2679-2690
ISSN
  • 0271-678X (ISSN-L)
  • 1559-7016
OpenAlex
W2619298813
Cited by
194
References
61
Citations by year
2026: 10 · 2025: 12 · 2024: 22 · 2023: 25 · 2022: 26 · 2021: 24 · 2020: 35 · 2019: 18 · 2018: 17 · 2017: 5
FWCI
10.22
Type
journal article
Language
en
Open access
Locations
  • Journal of Cerebral Blood Flow & Metabolism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • National Institute for Health and Care Research (NF-SI-0514-10022)
  • Multiple Sclerosis Society
  • Canadian Institutes of Health Research
  • Medical Research Council (MR/N008219/1, MR/N026934/1)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Keywords
TSPO, microglia, macrophages, pro-inflammatory activation, myeloid cell activation, monocyte-derived macrophages
MeSH terms
Acetamides, Adult, Animals, Brain, Cells, Cultured, Humans, Interferon-gamma, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Middle Aged, Protein Binding, Pyridines, Species Specificity, Gene Expression, Granulocyte-Macrophage Colony-Stimulating Factor, Microglia, Receptors, GABA, Myeloid Cells, Young Adult

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