Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

In the paper

“It is generally accepted that microglia and macrophages are the primary cell types exhibiting an increased number of TSPO binding sites in human pathologies, and that astrocytes are not significant contributors to increased TSPO binding sites [44;45].”

What the sources say

• Disputed

  Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  cites [44] Venneti S Lopresti BJ Wang G Hamilton RL Mathis CA Klunk WE Apte UM Wiley CA PK11195 labels activated microglia in Alzheimer’s disease and in vivo in a mouse model using PET Neurobiol Aging 2008 PMC2745919 18178291 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [45] Banati RB Goerres GW Myers R Gunn RN Turkheimer FE Kreutzberg GW Brooks DJ Jones T Duncan JS [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis Neurology 1999 53 2199 2203 10599809 source

In the paper

“Immunohistochemical determination of TSPO expression in the human CNS would be an adjunctive means of studying TSPO [14].”

What the sources say

• Partly supported

  In the section on PBR in CNS disease (page not provided), the review describes combining autoradiography with immunohistochemistry for astrocytes and microglia. It also calls for comparing human histopathologic data with ligand-binding studies. This supports histology as an adjunct, but the cited passages do not establish immunohistochemical determination of TSPO expression itself in the human CNS. (LLM, conf=0.82)

  cites [14] Venneti S Lopresti BJ Wiley CA The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging Prog Neurobiol 2006 80 308 322 17156911 PMC1849976 sourceExperimental — accuracy not yet measured

In the paper

“Traditional autoradiography studies of postmortem tissues confirm that TSPO binding sites are increased in many of these diseases and that these binding sites are primarily in microglia.”

What the sources say

• Supported

  The discussion of PBR expression in CNS disease (page unavailable) reports increased binding in a wide variety of neurological diseases and says that, in the majority of those studies, the increase localizes to activated microglia. The Summary (page unavailable) also says PBR increases with injury and neurodegeneration, predominantly in microglia, citing evidence from animal models and human postmortem tissues. (LLM, conf=0.89)

  cites [14] Venneti S Lopresti BJ Wiley CA The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging Prog Neurobiol 2006 80 308 322 17156911 PMC1849976 source
• Partly supported

  The Cellular source and function section (page unavailable) reports that microautoradiography finds increased PK11195 binding predominantly on activated microglia, though it also identifies binding on infiltrating blood-borne cells. The Dementia and Movement disorders sections describe increased binding in several neurodegenerative diseases, but chiefly from in vivo PET studies; the paper does not establish that postmortem autoradiography confirmed those increases across many such diseases. (LLM, conf=0.85)

  cites [15] Cagnin A Kassiou M Meikle SR Banati RB Positron emission tomography imaging of neuroinflammation Neurotherapeutics 2007 4 443 452 17599710 PMC7479716 sourceExperimental — accuracy not yet measured

In the paper

“Use of TSPO-binding radioligands to assess neuroinflammation via PET imaging indicates that they may have value as a biosensor of ongoing disease and may also be a target to reduce inflammation-mediated damage in diseases such as HIV-associated neurological disorders and dementia ([17] and see [15;18] for review).”

What the sources say

• ?Not checked — no full text of the sourcecites [17] Herholz K Carter SF Jones M Positron emission tomography imaging in dementia Br J Radiol 2007 80 Spec No 2 S160 S167 18445746 source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [15] Cagnin A Kassiou M Meikle SR Banati RB Positron emission tomography imaging of neuroinflammation Neurotherapeutics 2007 4 443 452 17599710 PMC7479716 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [18] Chen MK Guilarte TR Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair Pharmacol Ther 2008 118 1 17 18374421 PMC2453598 source

In the paper

“The pAb (but not mAb) labeled neuronal cell bodies with punctuate spots (B), and both pAb and mAb labeled some endothelial cells (F) and smooth muscle cells, in agreement with other studies [27;31].”

What the sources say

• ?Not checked — no full text of the sourcecites [27] Morgan J Oseroff AR Cheney RT Expression of the peripheral benzodiazepine receptor is decreased in skin cancers in comparison with normal skin Br J Dermatol 2004 151 846 856 15491426 source
• Partly supported

  The Pathologic Examination reports PBBS staining in endothelial and smooth muscle cells, supporting the cell types named in the claim. The Immunohistochemical Data section specifies a monoclonal antibody for this staining; our copy does not establish that a polyclonal antibody (pAb) also labeled those cells. (LLM, conf=0.87)

  cites [31] Tomasi G Edison P Bertoldo A Roncaroli F Singh P Gerhard A Cobelli C Brooks DJ Turkheimer FE Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer’s disease J Nucl Med 2008 49 1249 1256 18632810 sourceExperimental — accuracy not yet measured

In the paper

“Papadopoulos and colleagues have shown that the Sp1/Sp3 and members of the Ets family of transcription factors control basal expression of the TSPO [61].”

What the sources say

• Supported

  The Abstract states that Sp1/Sp3 and members of the Ets family bind the TSPO promoter and drive basal TSPO gene transcription. The Introduction also says their binding sites are important for basal promoter activity. Page numbers are not provided in our copy's passages. (LLM, conf=0.94)

  cites [61] Giatzakis C Batarseh A Dettin L Papadopoulos V The role of Ets transcription factors in the basal transcription of the translocator protein (18 kDa) Biochemistry 2007 46 4763 4774 17402746 PMC2529463 source

In the paper

“In the human CNS, microglia and endothelial cells have been shown to express TSPO readily ([31] and see [14] for review).”

What the sources say

• Supported

  The Discussion reports that PBBS is consistently upregulated in microglial cells reacting to brain injury. The Pathologic Examination reports strong PBBS expression in endothelial cells of arteries in young human brains; it also notes reduced vascular expression in elderly and Alzheimer’s brains. These passages support expression in both cell types, with expression varying by condition. (LLM, conf=0.86)

  cites [31] Tomasi G Edison P Bertoldo A Roncaroli F Singh P Gerhard A Cobelli C Brooks DJ Turkheimer FE Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer’s disease J Nucl Med 2008 49 1249 1256 18632810 source
• Partly supported

  Section 2.1.2 says PBR (TSPO) was detected in microglia, and section 2.1.3 discusses microglial PBR-ligand binding in brain tissue, including multiple sclerosis. The passages do not establish TSPO expression in endothelial cells of the human CNS, so that part of the claim is unsupported. (LLM, conf=0.84)

  cites [14] Venneti S Lopresti BJ Wiley CA The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging Prog Neurobiol 2006 80 308 322 17156911 PMC1849976 sourceExperimental — accuracy not yet measured

In the paper

“but TSPO+ astrocytes have been rarely observed in humans and are particularly noted in hepatic encephalopathy [48].”

What the sources say

• Partly supported

  The Discussion (page not specified in our copy) reports increased peripheral-type benzodiazepine receptor binding in brain samples from patients with hepatic encephalopathy and says this most likely reflects astrocytic changes. It does not establish that receptor-positive astrocytes were directly observed, or that they are rarely observed in humans. (LLM, conf=0.86)

  cites [48] Lavoie J Layrargues GP Butterworth RF Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy Hepatology 1990 11 874 878 2161396 sourceExperimental — accuracy not yet measured

In the paper

“Rarely, TSPO+ cells resembling oligodendrocytes were also observed (not shown, but see Figure 2 for macaque brains).”

In the paper

“The pAb (but not mAb) labeled neuronal cell bodies with punctuate spots (B), and both pAb and mAb labeled some endothelial cells (F) and smooth muscle cells, in agreement with other studies [27;31].”

In the paper

“In general, the mAb was better than the pAb in staining vessel-associated TSPO.”

In the paper

“The quality of the staining was punctate which is consistent with the reported mitochondrial localization of TSPO protein.”

In the paper

“Qualitatively, however, the staining intensity in some HIVE cases appears to be higher (not shown).”

In the paper

“The leukocyte marker CD45 also demonstrated double-positive perivascular macrophages as well as MGCs (Figure 4E, F).”

In the paper

“Of note, a CNS lymphoma in HIVE demonstrated tumour cells to be TSPO+, as well as the infiltrating macrophages and phagocytic microglia (not shown).”

In the paper

“In our study, TSPO+ astrocytes were present in all human disease states, but much less frequently than TSPO+ microglia, suggesting that astrocytic expression may be shorter-lived and/or it occurs only in a subset of astrocytes.”

In the paper

“Double labeling with the astrocyte marker GFAP showed that astrocytes can express TSPO (arrowheads, Figure 5A, D), but that astrocyte expression was not as widespread as microglial expression.”

In the paper

“An additional point of interest was that TSPO+ oligodendrocytes were present in the optic tract (and vicinity) in one SIVE and the SIV− brain (Figure 2E).”

In the paper

“Some nodules had very high TSPO labeling; the highest observed TSPO expression in the captured images was 4.7% area stained (which contributed to the large range shown for the HIVE cases).”

In the paper

“We find that these antibodies were both useful and generally had good agreement in their level of staining (see Figure 1 and Table 3), although there were some differences.”

In the paper

“The results show that TSPO+ vessels appeared in approximately one out of three 400X fields on average, with no differences observed between the groups (Figure 3C).”

In the paper

“In HIVE, TSPO levels ranged greatly such that some areas appeared to have low, normal-appearing TSPO expression while microglial nodules had very high levels of TSPO.”

In the paper

“We observed that TSPO+ vasculature was present in brains regardless of whether they were HIV−, HIV+ or HIVE and there does not seem to be a significant increase in HIVE brains, suggesting that unlike glial cell TSPO, endothelial TSPO might be constitutive.”

In the paper

“Most MGCs were CD68+ and TSPO+ (Figure 4B).”

In the paper

“The sections from brains with ischaemia were large and TSPO expression was limited to the lesion and areas juxtaposed to the lesion, but areas away from the lesion exhibited reduced, normal levels of TSPO (not shown).”

In the paper

“In addition, the brain areas adjacent to the infarct showed many positive hypertrophic TSPO+ astrocytes, as well as amoeboid microglia with punctate TSPO+ stain (Figure 6F & G).”

In the paper

“What were noticeably lacking in SIVE were the TSPO+ hypertrophic astrocytes that were present in most HIVE cases.”

In the paper

“The percent area stained between HIV− and HIV+ groups was not significantly different for either antibody.”

In the paper

“Adjacent brain showed neuronal staining as well as focal microglial staining.”

In the paper

“The percent area stained in the HIV+ group ranged from 0.01 to 0.10% for the mAb and 0.01 to 0.08% for the pAb.”

In the paper

“Our own preliminary data indicates that interleukin-1β can increase TSPO in primary human astrocytes (not shown).”

In the paper

“TMA ensured that the different brain tissues were subjected to identical staining conditions thus eliminating variables (S. Morgello et al., manuscript in preparation).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites S. Morgello et al., manuscript in preparation

In the paper

“The results are useful for informing the usage of PET as an imaging modality and have an impact on the potential use of TSPO as an anti-inflammatory pharmacological target.”

In the paper

“The quality of the staining was punctate which is consistent with the reported mitochondrial localization of TSPO protein.”

In the paper

“The TSPO staining in single-stained slides was first analyzed semi-quantitatively by two independent observers using a grading system from no staining (−) to high levels of intense staining across the slide (++++) in various cell types, with good agreement between the two observers.”

In the paper

“The HIVE cases with concurrent infections (one had neurosyphillis and had CNS lymphoma) were not used for image analysis.”

In the paper

“Cases of conditions other than HIV were not analyzed because corresponding normal controls were not available from each site.”

In the paper

“In the CNS, TSPO is thought to be expressed by activated microglia and, in addition, administration of the TSPO ligands in vivo or in vitro results in suppression of microglialactivation including inhibition of cytokine expression [12;13].”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Choi HB Khoo C Ryu JK van BE Kim SU McLarnon JG Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195 J Neurochem 2002 83 546 555 12390516 source
• ?Not checked — no full text of the sourcecites [13] Veiga S Carrero P Pernia O Azcoitia I Garcia-Segura LM Translocator protein 18 kDa is involved in the regulation of reactive gliosis Glia 2007 55 1426 1436 17674368 source

In the paper

“Additionally, since TSPO ligands have anti-inflammatory properties, suggesting a role for TSPO in neuroinflammation [12;13;22], an understanding of its cell type expression in various disease states may be a key resource in how to target the TSPO in these diseases.”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Choi HB Khoo C Ryu JK van BE Kim SU McLarnon JG Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195 J Neurochem 2002 83 546 555 12390516 source
• ?Not checked — no full text of the sourcecites [13] Veiga S Carrero P Pernia O Azcoitia I Garcia-Segura LM Translocator protein 18 kDa is involved in the regulation of reactive gliosis Glia 2007 55 1426 1436 17674368 source
• ?Not checked — no full text of the sourcecites [22] Ryu JK Choi HB McLarnon JG Peripheral benzodiazepine receptor ligand PK11195 reduces microglial activation and neuronal death in quinolinic acid-injected rat striatum Neurobiol Dis 2005 20 550 561 15916899 source

In the paper

“In the CNS, TSPO is thought to be expressed by activated microglia and, in addition, administration of the TSPO ligands in vivo or in vitro results in suppression of microglialactivation including inhibition of cytokine expression [12;13].”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Choi HB Khoo C Ryu JK van BE Kim SU McLarnon JG Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195 J Neurochem 2002 83 546 555 12390516 source
• ?Not checked — no full text of the sourcecites [13] Veiga S Carrero P Pernia O Azcoitia I Garcia-Segura LM Translocator protein 18 kDa is involved in the regulation of reactive gliosis Glia 2007 55 1426 1436 17674368 source

In the paper

“The results demonstrate that a variety of CNS cells are capable of expressing TSPO but that the pattern of expression differs between normal and diseased CNS, as well as among different diseases and cell types.”

In the paper

“The specificity of both antibodies has been confirmed by immunoblotting and subcellular localization has been verified by electron microscopy [27;28;54].”

What the sources say

• ?Not checked — no full text of the sourcecites [27] Morgan J Oseroff AR Cheney RT Expression of the peripheral benzodiazepine receptor is decreased in skin cancers in comparison with normal skin Br J Dermatol 2004 151 846 856 15491426 source
• ?Not checked — no full text of the sourcecites [28] Bribes E Carriere D Goubet C Galiegue S Casellas P Simony-Lafontaine J Immunohistochemical assessment of the peripheral benzodiazepine receptor in human tissues J Histochem Cytochem 2004 52 19 28 14688214 source
• ?Not checked — no full text of the sourcecites [54] Dussossoy D Carayon P Feraut D Belugou S Combes T Canat X Vidal H Casellas P Development of a monoclonal antibody to immuno-cytochemical analysis of the cellular localization of the peripheral benzodiazepine receptor Cytometry 1996 24 39 48 8723901 source

In the paper

“In our study, TSPO+ astrocytes were present in all human disease states, but much less frequently than TSPO+ microglia, suggesting that astrocytic expression may be shorter-lived and/or it occurs only in a subset of astrocytes.”

In the paper

“When the TSPO protein was incubated with the primary antibody, the glial cell staining was reduced to approximately half (52% by ImageJ) but the neuronal staining was not reduced (not shown).”

In the paper

“The experiment was not repeated because the cost of the peptide was prohibitive”

In the paper

“Neuronal expression of TSPO has been observed in rodents [35;36;55] but not in humans”

What the sources say

• ?Not checked — no full text of the sourcecites [35] Weissman BA Bolger GT Isaac L Paul SM Skolnick P Characterization of the binding of [3H]Ro 5–4864, a convulsant benzodiazepine, to guinea pig brain J Neurochem 1984 42 969 975 6321666 source
• ?Not checked — no full text of the sourcecites [36] Karchewski LA Bloechlinger S Woolf CJ Axonal injury-dependent induction of the peripheral benzodiazepine receptor in small-diameter adult rat primary sensory neurons Eur J Neurosci 2004 20 671 683 15255978 source
• ?Not checked — no full text of the sourcecites [55] Mills C Makwana M Wallace A Benn S Schmidt H Tegeder I Costigan M Brown RH Jr Raivich G Woolf CJ Ro5–4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats Eur J Neurosci 2008 27 937 946 18333964 source