The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory ‘M1’ human macrophages

Narayan, Nehal; Mandhair, Harpreet; Smyth, Erica; Dakin, Stephanie G.; Kiriakidis, Serafim; Wells, Lisa; Owen, David R.; Sabokbar, A; Taylor, Peter

doi:10.1371/journal.pone.0185767

Cited by 63 publications

(48 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As we previously described in detail (33), differentiation of monocytes to nonactivated macrophages (M0) significantly increased TSPO mRNA expression by a fold change of 60.7 6 2.38 (P , 0.05). Likewise, 3 H-PBR28 binding mirrored this significant increase, with specific binding of 1,004 6 52.61 fmol/1 · 10 6 cells for monocytes increasing to 1,838 6 45.37 fmol/1 · 10 6 cells for M0 macrophages (P , 0.01) ( Fig.…”

Section: In Vitro Evidence Of Tspo Expression In Cells Of Human Pannussupporting

confidence: 60%

“…Monocytes were differentiated from macrophages using recombinant human macrophage colony-stimulating factor (100 ng/mL; Peprotech Inc., U.K.) at a concentration of 1 · 10 6 monocytes/mL for 7 d (32), as previously described by Narayan et al (33). Fluorescence-activated cell sorting was used to confirm that monocytes had been differentiated to monocyte-derived macrophages (34).…”

Section: In Vitro Cell Culture Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

et al. 2018

Self Cite

View full text Add to dashboard Cite

PET radioligands targeted to translocator protein (TSPO) offer a highly sensitive and specific means of imaging joint inflammation in rheumatoid arthritis (RA). Through high expression of TSPO on activated macrophages, TSPO PET has been widely reported in several studies of RA as a means of imaging synovial macrophages in vivo. However, this premise does not take into account the ubiquitous expression of TSPO. This study aimed to investigate TSPO expression in major cellular constituents of RA pannus-monocytes, macrophages, fibroblastlike synoviocytes (FLS cells), and CD4-positive (CD4+) T lymphocytes (T cells)-to more accurately interpret TSPO PET signal from RA synovium. Three RA patients and 3 healthy volunteers underwent PET of both knees using the TSPO radioligandC-PBR28. Through H-PBR28 autoradiography and immunostaining of synovial tissue in 6 RA patients and 6 healthy volunteers, cellular expression of TSPO in synovial tissue was evaluated. TSPO messenger RNA expression andH-PBR28 radioligand binding was assessed using in vitro monocytes, macrophages, FLS cells, and CD4+ T cells. C-PBR28 PET signal was significantly higher in RA joints than in healthy joints (average SUV, 0.82 ± 0.12 vs. 0.03 ± 0.004; < 0.01). Further, H-PBR28-specific binding in synovial tissue was approximately 10-fold higher in RA patients than in healthy controls. Immunofluorescence revealed TSPO expression on macrophages, FLS cells, and CD4+ T cells. The in vitro study demonstrated the highest TSPO messenger RNA expression andH-PBR28-specific binding in activated FLS cells, nonactivated M0 macrophages, and activated M2 reparative macrophages, with the least TSPO expression being in activated and nonactivated CD4+ T cells. To our knowledge, this study was the first evaluation of cellular TSPO expression in synovium, with the highest TSPO expression and PBR28 binding being found on activated synovial FLS cells and M2 macrophages. TSPO-targeted PET may therefore have a unique sensitivity in detecting FLS cells and macrophage-predominant inflammation in RA, with potential utility for assessing treatment response in trials using novel FLS-cell-targeted therapies.

show abstract

Section: In Vitro Evidence Of Tspo Expression In Cells Of Human Pannussupporting

confidence: 60%

Section: In Vitro Cell Culture Studiesmentioning

confidence: 99%

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…(proinflammatory) macrophages and microglia may show lower TSPO expression in humans (58,59). The abovediscussed literature, together with the results of our study, challenges the utility of TSPO as an exclusively proinflammatory marker in schizophrenia.…”

Section: Meta-analysis Of Tspo In Patients With Psychosismentioning

confidence: 56%

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Plavén-Sigray

Matheson

Collste

et al. 2018

Biological Psychiatry

110

102

View full text Add to dashboard Cite

BACKGROUND: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects. METHODS: PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (V T ), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients' TSPO levels compared with healthy control subjects. RESULTS: Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower V T in patients relative to no difference (all BFs .

show abstract

“…Numerous preclinical studies show analgesic and anti-inflammatory effects of TSPO agonism, such as increased expression of anti-inflammatory IL-10 and other M2-related microglial genes, indicating that changes in TSPO expression might be an adaptive response to a homeostatic challenge (Bae et al, 2014; Liu et al, 2016; Wei et al, 2013). Similarly, recent in vitro human studies suggest that immune challenges induce TSPO upregulation in anti-inflammatory M2-like macrophages, and TSPO reduction in inflammatory M1-like macrophages (Narayan et al, 2017; Owen et al, 2017). We previously documented significantly higher CSF concentrations of IL-10 and other anti-inflammatory cytokines in FM patients, as opposed to a more classical (M1-like) pro-inflammatory CSF cytokine profile in patients with rheumatoid arthritis (RA; Kosek et al, 2015; Lampa et al, 2012).…”

Section: Discussionmentioning

confidence: 85%

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

Albrecht

Forsberg

Sandström

et al. 2019

Brain, Behavior, and Immunity

215

170

View full text Add to dashboard Cite

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C]--deprenyl-D PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C]PBR28 PET. 11 FM patients and 11 HC were scanned using [C]--deprenyl-D PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V) were computed from the [C]PBR28 data. [C]--deprenyl-D was quantified using λ k. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C]PBR28 V and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C]--deprenyl-D signal, including those demonstrating elevated [C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [C]PBR28 V and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C]PBR28 signal were not also accompanied by increased [C]--deprenyl-D signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C]--deprenyl-D signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

show abstract

The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory ‘M1’ human macrophages

Cited by 63 publications

References 68 publications

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

Contact Info

Product

Resources

About