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Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans
Open accessAbstract
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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“Recently, we have shown in vitro that, although TSPO gene and protein expression and TSPO radioligand binding increases in rodent microglia and macrophages with inflammatory stimulation, relative TSPO gene expression in human microglia and TSPO ligand binding in human monocyte-derived macrophages are reduced with pro-inflammatory activation (Owen et al., 2017).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Owen et al., 2017
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“Recently, we have shown in vitro that, although TSPO gene and protein expression and TSPO radioligand binding increases in rodent microglia and macrophages with inflammatory stimulation, relative TSPO gene expression in human microglia and TSPO ligand binding in human monocyte-derived macrophages are reduced with pro-inflammatory activation (Owen et al., 2017).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Owen et al., 2017
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“However, in humans, TSPO is not upregulated in either pro-inflammatory macrophages (Narayan et al., 2017) or primary microglia (Owen et al., 2017).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Owen et al., 2017
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“This new observation thus confirms in vitro data suggesting that the TSPO expression signal does not distinguish between microglial phenotypes in human tissue (Owen et al., 2017).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Owen et al., 2017
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“On the other hand, an in vitro study showed that TSPO expression did not increase in primary human microglia upon pro-inflammatory activation contrary to rodent microglia.(57) TSPO expression decreased during anti-inflammatory M2 microglial polarization in a mice model of brain hypoxia.”
BackgroundBlood–Brain Barrier Disruption and Imaging Assessment in Stroke
Liang, Y., Jiang, Y., Liu, J., Li, X., Cheng, X., Bao, L., Zhou, H.-W., & Guo, Z. (2024) · Translational Stroke Research · doi:10.1007/s12975-024-01300-6 · Cited by 19
“TSPO-PET is able to examine microglial activation in animal models and in clinical stroke, and TSPO expression has been associated with proinflammatory networks in rodents related, but in humans, TSPO is associated with microglia proliferation [85].”
Lopresti, B. J., Royse, S. K., Mathis, C. A., Tollefson, S., & Narendran, R. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15615 · Cited by 16
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Self-citationMeta-analytic studies of the glial cell marker TSPO in psychosis – a question of apples and pears?
Plavén‐Sigray, P., & Červenka, S. (2019) · Psychological Medicine · doi:10.1017/s003329171800421x · Cited by 17
“, 2017), and might even show decreased levels (Owen et al., 2017).”
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“The translocator protein 18 kDa (TSPO) is a mitochondrial membrane protein that is up-regulated in activated macrophages [6,7].”
BackgroundQuantification of [11C]PBR28 data after systemic lipopolysaccharide challenge
Woodcock, E. A., Schain, M., Cosgrove, K., & Hillmer, A. T. (2020) · EJNMMI Research · doi:10.1186/s13550-020-0605-7 · Cited by 14
“Limitations of this work include our inability to confirm whether LPS activates microglia and/or astrocytes and recruits additional TSPO-expressing cells, or any combination of these or other properties [22].”
BackgroundImaging of microglia in post-stroke inflammation
Wang, Z., Song, Y., Bai, S., Xiang, W., Zhou, X., Han, L., Zhu, D., & Guan, Y. (2023) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2023.108336 · Cited by 13
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Imaging the brain’s immune response to alcohol with [11C]PBR28 TSPO Positron Emission Tomography
Raval, N. R., Angarita, G. A., Matuskey, D., Miller, R., Drake, L. R., Kapinos, M., Nabulsi, N., Huang, Y. H., Carson, R. E., O’Malley, S. S., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02198-6 · Cited by 12
“…based on evidence that acute increases in TSPO radiotracer binding correspond to increases in the numbers of TSPO-expressing cells (primarily microglia in the brain), while TSPO expression per cell did not change [51], consistent with results from human macrophages and post-mortem tissue [52, 53].”
ResultNutma, E., Fancy, N. N., Weinert, M., Marzin, M. C., Tsartsalis, S., Muirhead, R. C. J., Falk, I. N., de Bruin, J., Hollaus, D., Pieterman, R., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.11.491453 · Cited by 13
Self-citationAndrew, P. M., MacMahon, J. A., Bernardino, P. N., Tsai, Y., Hobson, B. A., Porter, V. A., Huddleston, S. L., Luo, A., Bruun, D. A., Saito, N. H., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03272-8 · Cited by 13
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“These 1 st and 2 nd generation ligands, respectively, bind to the mitochondrial translocator protein 18-kDa (TSPO), which is abundant in activated macrophages, microglia, and astroglia (Chen & Guilarte, 2008; Owen et al., 2017; Papadopoulos et al., 2006).”
Schroyen, G., Sleurs, C., Bartsoen, E., Smeets, D., Weehaeghe, D. V., Laere, K. V., Smeets, A., Deprez, S., & Sunaert, S. G. (2022) · The Breast · doi:10.1016/j.breast.2022.02.001 · Cited by 11
Nwaubani, P., Cercignani, M., & Colasanti, A. (2022) · Clinical and Experimental Immunology · doi:10.1093/cei/uxac058 · Cited by 10
“In normal conditions, TSPO is highly expressed in peripheral tissues, particularly where steroids are synthesized, consistent with its role in steroidogenesis [36].”
BackgroundMenevse, A. N., Ammer, L.-M., Vollmann‐Zwerenz, A., Kupczyk, M., Lorenz, J., Weidner, L., Hussein, A., Sax, J., Mühlbauer, J., Heuschneider, N., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01550-9 · Cited by 14
“Immune-mediated regulation of TSPO expression in malignant cells has not been addressed so far, yet several groups reported contradicting results in mice and humans: IFNγ and LPS stimulation induced TSPO expression in rodent macrophages and microglia, whereas TSPO expression was strongly downregulated in primary human…”
Bader, S. M., Würfel, T., Jahner, T., Nothdurfter, C., Rupprecht, R., Milenkovic, V. M., & Wetzel, C. H. (2023) · Cells · doi:10.3390/cells12060954 · Cited by 12
“Activation of cells did not induce increased TSPO expression in human microglia but did so in rodent microglia [47].”
BackgroundThe Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?
Ellen, O., Ye, S., Nheu, D., Dass, M., Pagnin, M., Öztürk, E., Theotokis, P., Grigoriadis, N., & Petratos, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311112 · Cited by 11
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“dominantly myeloid cell number [12], FDG reflects overall metabolic activity.”
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“Moreover, recent studies suggest that TSPO may be down-regulated in activated microglia (Owen et al., 2017).”
BackgroundPositron emission tomography to image cerebral neuroinflammation in ischaemic stroke: a pilot study
Visi, E., Hinz, R., Punter, M. N. M., Majid, A., Gerhard, A., & Herholz, K. (2020) · Efficacy and Mechanism Evaluation · doi:10.3310/eme07010 · Cited by 9
Efficacy of retigabine in ameliorating the brain insult following sarin exposure in the rat
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PET Imaging of Neuroinflammation
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Imaging translocator protein expression with positron emission tomography
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“The cellular source of TSPO is highly dependent on species [1, 3, 4] and on the pathology or animal model.”
BackgroundPlavén‐Sigray, P., & Červenka, S. (2019) · Psychological Medicine · doi:10.1017/s0033291719000746 · Cited by 9
Advanced Brain Imaging in Central Nervous System Demyelinating Diseases
Cagol, A., Tsagkas, C., & Granziera, C. (2024) · Neuroimaging Clinics of North America · doi:10.1016/j.nic.2024.03.003 · Cited by 8
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“A study by (Owen et al. 2017) did not observe an increase in TSPO signal following pro-inflammatory activation of human brain microglia and suggested that elevated TSPO signal could reflect microglial density rather than microglial activation [40].”
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“While the cellular localization of the TSPO signal is not always certain, the near consensus of PET results is consistent with microglial activation or monocyte recruitment in brain of MDD patients [5,17].”
Result18 kDa Translocator Protein TSPO Is a Mediator of Astrocyte Reactivity
Tournier, B. B., Bouteldja, F., Amossé, Q., Nicolaides, A., Azevedo, M. D., Tenenbaum, L., Garibotto, V., Ceyzériat, K., & Millet, P. (2023) · ACS Omega · doi:10.1021/acsomega.3c03368 · Cited by 9
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“Moreover, TSPO expression within human microglia does not increase with classical pro-inflammatory versus anti-inflammatory states [69, 70].”
BackgroundMicroglia in autism spectrum disorder: heterogeneity, immunometabolism, and synapse-related pathways
Lian, A., He, M., Zhang, H., & Yang, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1783755 · Cited by 7
“…glia-associated neuroimmune signals in living individuals with ASD, but interpretation is complex because TSPO is not microglia speci fi c and because ligand binding, mitochondrial biology, genotype, psychiatric subgroup structure, and kinetic modeling all in fl uence the signal (16) (17, 18).”
Zatcepin, A., Heindl, S., Schillinger, U., Kaiser, L., Lindner, S., Bartenstein, P., Kopczak, A., Liesz, A., Brendel, M., & Ziegler, S. I. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.830020 · Cited by 6
“Microglia activation is strongly correlated to the 18 kDa translocator protein (TSPO) expression level on the outer membrane of microglial mitochondria (5).”
BackgroundBlum, N., Mirian, C., Maier, A. D., Mathiesen, T. I., Vilhardt, F., & Haslund-Vinding, J. L. (2023) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlad093 · Cited by 6
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Nanostructured Modulators of Neuroglia
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Impact of NBP on acute ischemic stroke: Tracking therapy effect on neuroinflammation
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Machado, L. S., Vidor, P. R., Perquim, L., Limberger, C., Machado, L., da Rocha, A. S., Soares, C., Rahmouni, N., Brum, W. S., Bellaver, B., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03160-4 · Cited by 5
“Indeed, it has been shown that changes in microglial phenotypes can trigger astrocyte reactivity [101].”
Neuroinflammation and Microglial Activation in Schizophrenia: An Overview
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Characteristics of TSPO expression in marmoset EAE
Falk, I., Maric, D., Leibovitch, E., Sati, P., Lefeuvre, J., Luciano, N. J., Guy, J., Ha, S.-K., Owen, D. R., Aigbirhio, F., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03343-4 · Cited by 5
“Each Iba1 + cell body was also then scanned for expression of early activation marker MRP14 [48], MHC-II molecule HLA-DR [20, 46], phagocytic receptor CD163 [50, 51], and Arg1, which is associated with immuno-suppression [49].”
Self-citationTSPO PET Imaging as a Biomarker of Neuroinflammation in Neurodegenerative Disorders
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Diagnostic utility of plasma translocator protein 18 kDa (TSPO) in sepsis: A case–control study
Hattori, M., Kikutani, K., Hosokawa, K., Kyo, M., Nishikimi, M., Ota, K., Ohshimo, S., Aizawa, H., & Shime, N. (2024) · Medicine · doi:10.1097/md.0000000000040396 · Cited by 4
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Yan, X., Siméon, F. G., Liow, J., Morse, C. L., Jana, S., Santamaria, J. A. M., Jenkins, M. D., Zoghbi, S. S., Pike, V. W., Innis, R. B., et al. (2024) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x241304924 · Cited by 3
Neurosteroids and Translocator Protein (TSPO) in neuroinflammation
Angeloni, E., Germelli, L., Costa, B., Martini, C., & Pozzo, E. D. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105916 · Cited by 5
Refining seizure foci localization: the potential of TSPO-PET
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“Thus, inflammation-induced activation of human microglia does not lead to increased TSPO expression [63, 64] (Fig.”
Imaging Neuroimmune Dysfunction: From TSPO to Emerging Positron Emission Tomography Targets
Bonomi, R. E., Raval, N. R., Hillmer, A. T., & Cosgrove, K. (2025) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.11.010 · Cited by 3
A Macrophage-Specific PET Tracer for Grading Acute Liver Injury
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“Elevated binding may also re fl ect myeloid proliferation or peripheral monocyte recruitment, adding interpretive uncertainty [152, 153].”
Deniel, G., Dhelft, F., Lancelot, S., Orkisz, M., Roux, E., Mouton, W., Benzerdjeb, N., Richard, J., & Bitker, L. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1338602 · Cited by 2
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Neural biomarkers of suicidal behavior: from cognition and circuits to cells (and back)
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Microglia and Psychiatric Disorders
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“Differences not only relate to their transcriptome, but also in the way cells react to insults, such as morphological alterations and nitric oxide synthesis in response to interferon/LPS treatment (Geirsdottir et al., 2019; Gosselin et al., 2017; Healy, Yaqubi, Ludwin, & Antel, 2019; Owen et al., 2017).”
BackgroundSelf-citationNeuroimaging Modalities in Neuroimmunology
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“For example, Owen et al. (2017) demonstrated that, in a murine model, LPS stimulation significantly upregulated TSPO expression in hippocampal microglia [29].”
Peripheral biomarkers of neuroinflammation in Alzheimer’s disease and vascular dementia
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The Effect of Systemic Inflammation on Cognitive Function and Neurodegenerative Disease
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Neuroinflammation and Microglial Activation in Schizophrenia: An Overview
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Adventures in Translocation: Studies of the Translocator Protein (TSPO) 18 kDa*
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Astroglial Pathology in Major Depressive Disorders: Metabolic and Molecular Aspects
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MerTK mediates the immunologically silent uptake of alpha-synuclein fibrils by human microgliaPreprint
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Translocator protein (18 kDa TSPO) binding in depression
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Etifoxine inhibits NLRP3 inflammasome activity in human and murine myeloid cellsPreprint
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Extra-axial inflammatory signal and its relation to peripheral and central immunity in depressionPreprint
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“…nervous system but emerging data suggests that reactive astrocytes may also have a contributory role to TSPO expression signals (Lavisse et al. 2012) and it is becoming increasingly recognised that [ 11 C] PBR28 binding can represent pro-, anti-and mixed inflammatory phenotypes (Owen et al. 2017).”
Self-citationPost-Mortem validation of in vivo 18kDa Translocator Protein (TSPO) PET as a microglial biomarkerPreprint
Wijesinghe, S. S., Rowe, J. B., Mason, H. D., Allinson, K. S. J., Thomas, R., Vontobel, D. S., Fryer, T. D., Hong, Y. T., Bacioglu, M., Spillantini, M. G., et al. (2024) · medRxiv · doi:10.1101/2024.07.15.24309178
“For example, TSPO expression does not always increase in response to inflammatory or neurotoxic stimuli 24,25 , and in AD and multiple sclerosis post-mortem tissue studies, increased TSPO expression has been observed in endothelium and astrocytes 26,27 .”
BackgroundMelanocortin Receptor-Mediated Anti-Inflammatory Effect of Acthar® Gel in Human Myeloid Cells
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“This protocol has been reported to yield ≥ 90% microglia purity via CD11c staining by flow cytometry [21].”
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“Using positron emission tomography (PET) and radioligands such as [ 11 C]PBR28, TSPO can be imaged in-vivo, and elevations in TSPO signal during (neuro)inflammatory processes were shown to be proportional to glial/immune cell density [100–102].”
[18F]DPA-714 PET in presurgical evaluation of drug-resistant epilepsy: from clinical to pathology
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“This paradigm helps reconcile seemingly conflicting data [28] and implies that the TSPO PET signal in epilepsy captures a critical nexus of neuroimmune and metabolic dysfunction driving seizure pathogenesis.”
Rao, X., Yang, H., Chen, Y., Zhao, A., Cheng, T., Li, L., Zhang, Y., Li, X., & Li, Z. (2026) · Odontology · doi:10.1007/s10266-026-01487-0
Torrado-Carvajal, Á., & Loggia, M. L. (2026) · European Journal of Pain · doi:10.1002/ejp.70324
“Instead of being a marker of a specific activation phenotype or cellular state, TSPO is now understood to serve more as a marker of glial cell density (Nutma et al. 2021; Owen et al. 2017; Wijesinghe et al. 2025).”
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
- ORCID
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2017-05-22
- Volume
- 37
- Issue
- 8
- Pages
- 2679-2690
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC5536262
- 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
- hybrid
- doi.org
- 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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