Cited by 28Neuroinflammation and Neurodegeneration MechanismsMedical Imaging Techniques and ApplicationsPharmacological Receptor Mechanisms and Effects

Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation

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Vicente-Rodríguez, Marta, Singh, Nisha, Turkheimer, Federico, Peris-Yague, Alba, Randall, Karen, Veronese, Mattia, Simmons, Camilla, Karim Haji-Dheere, Abdul +7 more·2021·Brain, Behavior, and Immunity

Abstract

The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. One reason for this could be because the interpretation of TSPO PET signal remains challenging, given the cellular heterogeneity and ubiquity of TSPO in the brain. The aim of the current study was to ascertain if TSPO PET imaging can be used to detect neuroinflammation induced by a peripheral treatment with a low dose of the endotoxin, lipopolysaccharide (LPS), in a rat model (ip LPS), and investigate the origin of TSPO signal changes in terms of their cellular sources and regional distribution. An initial pilot study utilising both [18F]DPA-714 and [11C]PK11195 TSPO radiotracers demonstrated [18F]DPA-714 to exhibit a significantly higher lesion-related signal in the intracerebral LPS rat model (ic LPS) than [11C]PK11195. Subsequently, [18F]DPA-714 was selected for use in the ip LPS study. Twenty-four hours after ip LPS, there was an increased uptake of [18F]DPA-714 across the whole brain. Further analyses of regions of interest, using immunohistochemistry and RNAscope Multiplex fluorescence V2 in situ hybridization technology, showed TSPO expression in microglia, monocyte derived-macrophages, astrocytes, neurons and endothelial cells. The expression of TSPO was significantly increased after ip LPS in a region-dependent manner: with increased microglia, monocyte-derived macrophages and astrocytes in the substantia nigra, in contrast to the hippocampus where TSPO was mostly confined to microglia and astrocytes. In summary, our data demonstrate the robust detection of peripherally-induced neuroinflammation in the CNS utilising the TSPO PET radiotracer, [18F]DPA-714, and importantly, confirm that the resultant increase in TSPO signal increase arises mostly from a combination of microglia, astrocytes and monocyte-derived macrophages.

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  • TSPO is expressed in almost all CNS cells, including astrocytes, neurons and endothelial cells.

    “Although increased TSPO expression has historically been mostly associated with microglial activation, TSPO is now known to be expressed in almost all CNS cells including astrocytes, neurons and endothelial cells [21–27], all of which may also be involved in, or be affected by neuroinflammation [28].”

    From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [21]

    The Results section confirms TSPO expression in astrocytes, neurons and endothelial cells in the rat brain regions examined; the Introduction also describes TSPO in various other brain cells. The paper does not establish the broader claim that it is expressed in almost all CNS cells. Page numbers were not available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • In the LPS-challenged rat model, TSPO signal increased significantly in astrocytes and microglia upon inflammatory insult.

    “our previous study examining cellular sources of TSPO in a rodent model of acute neuroinflammation, the LPS-challenged rat, also found a similar diversity of source of TSPO signal which was present in all examined cells at baseline, but then increased significantly in astrocytes and microglia upon inflammatory insult [21].”
  • In a previous study of LPS-challenged rats (a rodent model of acute neuroinflammation), TSPO signal was present in all examined cells at baseline.

    “our previous study examining cellular sources of TSPO in a rodent model of acute neuroinflammation, the LPS-challenged rat, also found a similar diversity of source of TSPO signal which was present in all examined cells at baseline, but then increased significantly in astrocytes and microglia upon inflammatory insult [21].”

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Authors
Vicente-Rodríguez, M., Singh, N., Turkheimer, F., Peris-Yague, A., Randall, K., Veronese, M., Simmons, C., Karim Haji-Dheere, A., Bordoloi, J., Sander, K., Awais, R. O., Årstad, E., NIMA Consortium, Cash, D., & Parker, C. A.
Affiliations
  • King's College London (GB)
  • University College London (GB)
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2021-08
Volume
96
Pages
154-167
ISSN
0889-1591 (ISSN-L)
OpenAlex
W3164352382
Cited by
28
References
17
Citations by year
2026: 6 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 1
FWCI
2.00
Type
journal article
Language
en
Open access
Locations
  • Brain Behavior and Immunity (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • CEU Repositorio Institucional (Fundación Universitaria San Pablo CEU) (submittedVersion, cc-by-nc-nd)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
Wellcome Trust
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
Keywords
translocator protein (TSPO), neuroinflammation, lipopolysaccharide, peripheral immune activation, [18F]DPA-714, [11C]PK11195, TSPO PET imaging, microglia, monocyte-derived macrophages, astrocytes, substantia nigra, hippocampus, rat model
MeSH terms
Animals, Brain, Carrier Proteins, Pilot Projects, Receptors, GABA-A, Microglia, Receptors, GABA, Endothelial Cells, Positron-Emission Tomography, Rats

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