Increased Expression of Translocator Protein (TSPO) Marks Pro-inflammatory Microglia but Does Not Predict Neurodegeneration

Beckers, Lien; Ory, Dieter; Geric, Ivana; Declercq, Lieven; Koole, Michel; Kassiou, Michael; Bormans, Guy; Baes, Myriam

doi:10.1007/s11307-017-1099-1

Cited by 82 publications

(77 citation statements)

References 47 publications

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“…In accord with our findings, Beckers et al () very recently showed increased microglial TSPO expression in pro‐inflammatory activated microglia in vitro. These authors also demonstrated TSPO upregulation in a transgenic mouse strain that displays widespread neuroinflammation, and which the authors link to a pro‐inflammatory microglial phenotype.…”

Section: Discussionsupporting

confidence: 94%

“…In accord with our findings, Beckers et al (2018) very recently showed increased microglial TSPO expression in pro-inflammatory activated upregulation in a transgenic mouse strain that displays widespread neuroinflammation, and which the authors link to a pro-inflammatory microglial phenotype. However, in a previous study the proliferative microglia from this transgenic strain were shown to display a mixed pro-and anti-inflammatory phenotype (Verheijden et al, 2015).…”

Section: Tspo Upregulation Reflects Pro-inflammatory Microglia/macrsupporting

confidence: 92%

“…Reactive astrocytes have also been found to overexpress TSPO after striatal injection of a lentiviris encoding the ciliary neurotrophic factor (CNTF) gene, while microglia did not show a noticeable increase (Lavisse et al, 2012) Despite the established existence of different inflammatory phenotypes in glial cells, the extent to which TSPO upregulation reflects a pro-or anti-inflammatory phenotype remains unclear. Two recent studies attempted to address this question, but with conflicting results, and in both cases only the microglial/macrophage populations were assessed (Beckers et al, 2018;Owen et al, 2017). Yet it is known that both astrocytes and microglia contribute to neurological disease, and the nature of their contribution depends critically on their inflammatory phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia

Pannell

Economopoulos

Wilson

et al. 2019

Glia

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Translocator protein (TSPO) expression is increased in activated glia, and has been used as a marker of neuroinflammation in PET imaging. However, the extent to which TSPO upregulation reflects a pro‐ or anti‐inflammatory phenotype remains unclear. Our aim was to determine whether TSPO upregulation in astrocytes and microglia/macrophages is limited to a specific inflammatory phenotype. TSPO upregulation was assessed by flow cytometry in cultured astrocytes, microglia, and macrophages stimulated with lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin‐4 (Il‐4). Subsequently, mice were injected intracerebrally with either a TNF‐inducing adenovirus (AdTNF) or IL‐4. Glial expression of TSPO and pro‐/anti‐inflammatory markers was assessed by immunohistochemistry/fluorescence and flow cytometry. Finally, AdTNF or IL‐4 injected mice underwent PET imaging with injection of the TSPO radioligand 18F‐DPA‐713, followed by ex vivo autoradiography. TSPO expression was significantly increased in pro‐inflammatory microglia/macrophages and astrocytes both in vitro, and in vivo after AdTNF injection (p < .001 vs. control hemisphere), determined both histologically and by FACS. Both PET imaging and autoradiography revealed a significant (p < .001) increase in 18F‐DPA‐713 binding in the ipsilateral hemisphere of AdTNF‐injected mice. In contrast, no increase in either TSPO expression assessed histologically and by FACS, or ligand binding by PET/autoradiography was observed after IL‐4 injection. Taken together, these results suggest that TSPO imaging specifically reveals the pro‐inflammatory population of activated glial cells in the brain in response to inflammatory stimuli. Since the inflammatory phenotype of glial cells is critical to their role in neurological disease, these findings may enhance the utility and application of TSPO imaging.

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Section: Discussionsupporting

confidence: 94%

Section: Tspo Upregulation Reflects Pro-inflammatory Microglia/macrsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia

Pannell

Economopoulos

Wilson

et al. 2019

Glia

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“…Studies have also described that TSPO was not detectable in oligodendrocytes stained by anti-MBP-antibody or CD11b-positive microglia of a healthy brain [38,41]. Increased TSPO expression, however, was detected in a pro-inflammatory brain environment [42]. For example, in acute multiple sclerosis (MS), the majority of TSPO-positive cells were macrophages and microglia.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Cai

Kirchleitner

Zhao

et al. 2020

IJMS

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Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques. Therefore, we investigated the expression of TSPO and LAT1 in patient glioblastoma (GBM) samples, as well as in various GBM mouse models representing patient GBMs of different genetic subtypes. By immunohistochemistry, we found that TSPO and LAT1 are upregulated in human GBM samples compared to normal brain tissue. Next, we orthotopically implanted patient-derived GBM cells, as well as genetically engineered murine GBM cells, representing different genetic subtypes of the disease. To determine TSPO and LAT1 expression, we performed immunofluorescence staining. We found that both TSPO and LAT1 expression was increased in tumor regions of the implanted human or murine GBM cells when compared to the neighboring mouse brain tissue. While LAT1 was largely restricted to tumor cells, we found that TSPO was also expressed by microglia, tumor-associated macrophages, endothelial cells, and pericytes. The Cancer Genome Atlas (TCGA)-data analysis corroborates the upregulation of TSPO in a bigger cohort of GBM patient samples compared to tumor-free brain tissue. In addition, AIF1 (the gene encoding for the myeloid cell marker Iba1) was also upregulated in GBM compared to the control. Interestingly, TSPO, as well as AIF1, showed significantly different expression levels depending on the GBM genetic subtype, with the highest expression being exhibited in the mesenchymal subtype. High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression. In line with this finding, the expression levels for TSPO and AIF1 were also significantly higher in (isocitrate-dehydrogenase wild-type) IDHWT compared to IDH mutant (IDHMUT) GBM. LAT1 expression, on the other hand, was not different among the individual GBM subtypes. Therefore, we could conclude that FET- and TSPO-PET confer different information on pathological features based on different genetic GBM subtypes and may thus help in planning individualized strategies for brain tumor therapy in the future. A combination of TSPO-PET and FET-PET could be a promising way to visualize tumor-associated myeloid cells and select patients for treatment strategies targeting the myeloid compartment.

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“…Similarly, post‐mortem brain tissue from patients with malignant gliomas, cerebrovascular disease, and multiple sclerosis showed dramatic elevations of [ 3 H]PK11195 binding compared to tissue from healthy controls and increases in binding corresponded well to areas of damage (Benavides et al., ). Moreover, elevations of TSPO correlate well with astrocytic (Lavisse et al, , Dickens et al, ), and microglial activation (Beckers et al., ; Dickens et al, ; Hannestad et al, ), and specifically with the proinflammatory, but not the anti‐inflammatory phenotypes of activated microglia (Beckers et al., ).…”

Section: Introductionmentioning

confidence: 98%

Detecting neuroinflammation in the brain following chronic alcohol exposure in rats: A comparison between in vivo and in vitro TSPO radioligand binding

Tyler

Kim

Guo

et al. 2019

Eur J of Neuroscience

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Excessive alcohol consumption is associated with neuroinflammation, which likely contributes to alcohol‐related pathology. However, positron emission tomography (PET) studies using radioligands for the 18‐kDa translocator protein (TSPO), which is considered a biomarker of neuroinflammation, reported decreased binding in alcohol use disorder (AUD) participants compared to controls. In contrast, autoradiographic findings in alcohol exposed rats reported increases in TSPO radioligand binding. To assess if these discrepancies reflected differences between in vitro and in vivo methodologies, we compared in vitro autoradiography (using [3H]PBR28 and [3H]PK11195) with in vivo PET (using [11C]PBR28) in male, Wistar rats exposed to chronic alcohol‐vapor (dependent n = 10) and in rats exposed to air‐vapor (nondependent n = 10). PET scans were obtained with [11C]PBR28, after which rats were euthanized and the brains were harvested for autoradiography with [3H]PBR28 and [3H]PK11195 (n = 7 dependent and n = 7 nondependent), and binding quantified in hippocampus, thalamus, and parietal cortex. Autoradiography revealed significantly higher binding in alcohol‐dependent rats for both radioligands in thalamus and hippocampus (trend level for [3H]PBR28) compared to nondependent rats, and these group differences were stronger for [3H]PK11195 than [3H]PBR28. In contrast, PET measures obtained in the same rats showed no group difference in [11C]PBR28 binding. Our in vitro data are consistent with neuroinflammation associated with chronic alcohol exposure. Failure to observe similar increases in [11C]PBR28 binding in vivo suggests the possibility that a mechanism mediated by chronic alcohol exposure interferes with [11C]PBR28 binding to TSPO in vivo. These data question the sensitivity of PBR28 PET as a methodology to assess neuroinflammation in AUD.

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Increased Expression of Translocator Protein (TSPO) Marks Pro-inflammatory Microglia but Does Not Predict Neurodegeneration

Abstract: We show that induced TSPO expression marks a pro-inflammatory brain environment that is not necessarily accompanied by neuronal loss.

Cited by 82 publications

References 47 publications

Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia

Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Detecting neuroinflammation in the brain following chronic alcohol exposure in rats: A comparison between in vivo and in vitro TSPO radioligand binding

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