The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory ‘M1’ human macrophages
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The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or 'M1' phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-β1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages.
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In humans, TSPO is not upregulated in either pro-inflammatory macrophages or primary microglia.
“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 Narayan 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) .”
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“In addition, it is not clear whether targeting TSPO in macrophages is selective for M1 or M2 phenotypes, with previous evidence being conflicted on this aspect (6,55,56).”
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“On the other hand, recent in vitro work investigated TSPO expression in activated macrophages and surprisingly, a consistent downregulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or “M1” phenotype was demonstrated (35).”
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“Another study revealed that pro-inflammatory stimulation elicits a dose-dependent decrease in tspo mRNA and TSPO levels in the macrophages of patients with rheumatoid arthritis, whereas anti-inflammatory stimulation produces no change in TSPO levels (Narayan et al., 2017).”
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“We previously reported that activation of macrophages to a more M2 phenotype in the presence of IL-4 does not significantly alter TSPO expression (33), yet activation to an M1 phenotype (19) was found to significantly downregulate both TSPO mRNA and specific binding of 3H-PBR28.”
BackgroundInfluentialSelf-citationPlavén‐Sigray, P., Matheson, G. J., Coughlin, J. M., Hafizi, S., Laurikainen, H., Ottoy, J., Picker, L. D., Rusjan, P., Hietala, J. A., Howes, O. D., et al. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.05.028 · Cited by 50 · see citing works
“While TSPO has been shown to be sensitive in systemic inflammation paradigms (22,23), TSPO is not specific to microglia (24,25), and in vitro data have shown a lack of correspondence between TSPO and proinflammatory activation (26,27), although conflicting data exist (28,29).”
BackgroundMicroglia immunometabolism: From metabolic disorders to single cell metabolism
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Microglial activation in schizophrenia: Is translocator 18 kDa protein (TSPO) the right marker?
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“M1 macrophages have the unique ability to metabolize arginine to the “harmful” molecule NO, whereas M2 macrophages can metabolize arginine to the “repair” molecule ornithine [8].”
BackgroundMeta-analysis of molecular imaging of translocator protein in major depression
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PET Evaluation of Microglial Activation in Non-neurodegenerative Brain Diseases
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Perspective: Solving the Heterogeneity Conundrum of TSPO PET Imaging in Psychosis
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“Conversely, stimulation of macrophages to an “M2” phenotype with IL-4, dexamethasone or TGF-b1 did not alter TSPO expression (58).”
BackgroundExamining Immunotherapy Response Using Multiple Radiotracers
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“Furthermore, [(18)F]FEPPA tumour uptake did not correlate to changes in tumour-associated macrophages, most likely because the observed changes in the macrophage populations were small and TSPO levels have been shown to vary depending on polarisation [20].”
BackgroundSandström, A., Torrado-Carvajal, Á., Morrissey, E. J., Kim, M., Alshelh, Z., Zhu, Y., Li, M., Chang, C. Y., Jarraya, M., Akeju, O., et al. (2023) · Pain · doi:10.1097/j.pain.0000000000003114 · Cited by 18 · see citing works
Radiotracers for Imaging of Inflammatory Biomarkers TSPO and COX-2 in the Brain and in the Periphery
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“Some studies failed to show the upregulation in TSPO mRNA in human activated microglia ex vivo, but the results were heterogeneous and not specific to schizophrenia.(69,70)”
ResultNutrients and Immunometabolism: Role of Macrophage NLRP3
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Meta-analytic studies of the glial cell marker TSPO in psychosis – a question of apples and pears?
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“In vitro assays of human immune cells have shown that TSPO does not increase upon stimulation with the pro-inflammatory agent lipopolysaccharide (Narayan et al., 2017), and might even show decreased levels (Owen et al.”
BackgroundHou, Z., Wang, Q., Guo, Z., Wang, T., Wu, H., Ma, C., Wang, W., Su, F., Zhang, H., & Su, X. (2019) · Journal of drug targeting · doi:10.1080/1061186x.2019.1669040 · Cited by 15 · see citing works
“The translocator protein 18 kDa (TSPO) is a mitochondrial membrane protein that is up-regulated in activated macrophages [6,7].”
BackgroundWagner, T. R., Blaess, S., Leske, I. B., Frecot, D. I., Gramlich, M., Traenkle, B., Kaiser, P. D., Seyfried, D., Maier, S. M., Rezza, A., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1264179 · Cited by 14 · see citing works
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Selective Imaging of Lung Macrophages Using [11C]PBR28-Based Positron Emission Tomography
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“monocytes demonstrated downregulation of TSPO in M1 conditions but demonstrated no change under M2 conditions [35].”
Menevse, 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 11 · see citing works
“Similar results were demonstrated by another group where TSPO expression was strongly downregulated in human macrophages that were differentiated into the pro-inflammatory “M1” phenotype, whereas differentiation into the “M2” phenotype did not alter TSPO expression [64].”
Tuominen, S., Keller, T., Petruk, N., Lopez‐Picon, F. R., Eichin, D., Löyttyniemi, E., Verhassel, A., Rajander, J., Sandholm, J. A., Tuomela, J. M., et al. (2020) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-020-05115-z · Cited by 11 · see citing works
“[36] the authors demonstrated that monocytes in general express lower TSPO protein and mRNA levels than macrophages.”
BackgroundCross-Talk and Subset Control of Microglia and Associated Myeloid Cells in Neurological Disorders
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Microglia and major depression: not yet a clear picture
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“Moreover, a recent paper reports that the TSPO is downregulated on pro-inflammatory ‘M1’ human macrophages [59].”
BackgroundImmunomodulatory effect of lithium treatment on in vitro model of neuroinflammation
Sakrajda, K., Langwiński, W., Stachowiak, Z., Ziarniak, K., Narożna, B., & Szczepankiewicz, A. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110238 · Cited by 9 · see citing works
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“…of lipopolysaccharide (LPS; PreproTech, Hamburg, Germany, 100 ng/mL) and interferon gamma (IFNγ; Gibco, Gaithersburg, MD, USA, 20 ng/mL) 12,21 whereas the combination for M2 macrophages contained interleukin-4 (IL-4; Preprotech, Hamburg, Germany, 20 ng/mL) and IL-13 (Preprotech, Hamburg,…”
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PET imaging for the early evaluation of ocular inflammation in diabetic rats by using [18F]-DPA-714
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Microglia in autism spectrum disorder: heterogeneity, immunometabolism, and synapse-related pathways
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“…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).”
Blum, 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 · see citing works
Recent Advances in the Molecular Imaging of Atherosclerosis
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“investigated TSPO expression in human macrophages and found a significant difference in TSPO expression between M1 and M2 phenotypes [31].”
BackgroundCharacteristics 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 · see citing works
“Whereas multiple rodent studies have found increased TSPO mRNA levels in lipopolysaccharide (LPS)-stimu- lated microglia [15–17], a 2017 study of human macrophages found reduced TSPO protein and mRNA levels after LPS-stimulation [18].”
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
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“[10,11] We diagnosed sepsis and septic shock using the Sepsis–3 criteria.”
BackgroundMethodStammes, M. A., Koopman, G., Wagner, T. R., Traenkle, B., Kaiser, P. D., Mooij, P., van der Werff, N., Acar, R. F., Böszörményi, K. P., Blaess, S., et al. (2025) · Journal of Nuclear Medicine · doi:10.2967/jnumed.125.269721 · Cited by 4 · see citing works
“Moreover, we revealed enhanced [ 64 Cu]Cu-SIRP a -Nb uptake in the bone marrow at the later imaging time points (24 and 52 d after infection) as a potential measure of chronic in fl ammatory processes, as described for long COVID ( 6 ).”
Tollefson, S., Himes, M. L., Kozinski, K. M., Lopresti, B. J., Mason, N. S., Hibbeln, J. R., Muldoon, M. F., & Narendran, R. (2021) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2021.09.005 · Cited by 4 · see citing works
Choroid plexus alterations in autism spectrum disorder: A PET-MRI study
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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].”
Acetyl-L-carnitine attenuates Poly I:C-induced sickness behavior in mice
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Neuroimaging Modalities in Neuroimmunology
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“Although type-2 anti-inflammatory macrophages appear associated with TB disease progression [33, 34], paradoxically TSPO was found down-regulated in pro-inflammatory type-1 macrophages [35].”
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“Depending on the activation state, macrophages express various proteins that may be used as imaging target such as the folate receptor β [11], mannose receptor (also known as CD206) [12] and translocator protein (TSPO) [13].”
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TSPO Imaging in Psychiatric Disorders
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Post-Infarction Inflammatory Alterations
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TSPO in systemic-ocular immunometabolic crosstalk: mechanisms and therapeutic implications
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“Meanwhile, it can also be downregulated during classical pro-in fl ammatory activation in human macrophage, whereas the tested M2 stimuli did not signi fi cantly alter its expression (32).”
- Authors
- Narayan, N., Mandhair, H., Smyth, E., Dakin, S. G., Kiriakidis, S., Wells, L., Owen, D., Sabokbar, A., & Taylor, P.
- Affiliations
- University of Oxford (GB)
- Imperial College London (GB)
- Corresponding author
- Narayan, Nehal
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-10-02
- Volume
- 12
- Issue
- 10
- Pages
- e0185767
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5624624
- OpenAlex
- W2761467979
- Cited by
- 79
- References
- 69
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 5 · 2022: 8 · 2021: 10 · 2020: 16 · 2019: 13 · 2018: 8
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- NIHR BRC (OXF141232)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- translocator protein (TSPO), macrophage polarization, M1 macrophages, M2 macrophages, monocyte-derived macrophages, rheumatoid arthritis, THP-1 cells, inflammation, IL-4, dexamethasone, TGF-β1, TSPO PET imaging
- MeSH terms
- Arthritis, Rheumatoid, Cell Line, Humans, Inflammation, Interferon-gamma, Lipopolysaccharides, Macrophages, Monocytes, RNA, Messenger, Down-Regulation, Interleukin-4, Receptors, GABA, Positron-Emission Tomography, Real-Time Polymerase Chain Reaction
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