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Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain

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Title: Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain
Authors: Nutma, E
Gebro, E
Marzin, MC
Van der Valk, P
Matthews, PM
Owen, DR
Amor, S
Item Type: Journal Article
Abstract: To monitor innate immune responses in the CNS, the 18 kDa Translocator protein (TSPO) is a frequently used target for PET imaging. The frequent assumption that increased TSPO expression in the human CNS reflects pro-inflammatory activation of microglia has been extrapolated from rodent studies. However, TSPO expression does not increase in activated human microglia in vitro. Studies of multiple sclerosis (MS) lesions reveal that TSPO is not restricted to pro-inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia. Here, we investigated quantitative relationships between TSPO expression and microglia/macrophage phenotypes in white matter and lesions of brains with MS pathology. In white matter from brains with no disease pathology, normal appearing white matter (NAWM), active MS lesions and chronic active lesion rims, over 95% of TSPO+ cells are microglia/macrophages. Homeostatic microglial markers in NAWM and control tissue are lost/reduced in active lesions and chronic active lesion rims, reflecting cell activation. Nevertheless, pixel analysis of TSPO+ cells (n = 12,225) revealed that TSPO expression per cell is no higher in active lesions and chronic active lesion rims (where myeloid cells are activated) relative to NAWM and control. This data suggests that whilst almost all the TSPO signal in active lesions, chronic active lesion rims, NAWM and control is associated with microglia/macrophages, their TSPO expression predominantly reflects cell density and not activation phenotype. This finding has implications for the interpretation of TSPO PET signal in MS and other CNS diseases, and further demonstrates the limitation of extrapolating TSPO biology from rodents to humans.
Issue Date: Oct-2021
Date of Acceptance: 9-Jun-2021
URI: http://hdl.handle.net/10044/1/90379
DOI: 10.1002/glia.24052
ISSN: 0894-1491
Publisher: WILEY
Start Page: 2447
End Page: 2458
Journal / Book Title: GLIA
Volume: 69
Issue: 10
Copyright Statement: © 2021 The Authors. GLIA published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Sponsor/Funder: Medical Research Council (MRC)
National Institute for Health Research
UK DRI Ltd
UK DRI Ltd
Medical Research Council (MRC)
Funder's Grant Number: MR/N026934/1
RDA26
4050641385
DRI-DSI2020-001
MR/N008219/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
CD68
HLA-DR
IBA-1
microglia
multiple sclerosis
P2ry12
TSPO
PERIPHERAL BENZODIAZEPINE
BINDING
LESIONS
WHITE
PET
LOCALIZATION
INFLAMMATION
MACROPHAGES
PATHOLOGY
DISEASE
CD68
HLA-DR
IBA-1
P2ry12
TSPO
microglia
multiple sclerosis
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
CD68
HLA-DR
IBA-1
microglia
multiple sclerosis
P2ry12
TSPO
PERIPHERAL BENZODIAZEPINE
BINDING
LESIONS
WHITE
PET
LOCALIZATION
INFLAMMATION
MACROPHAGES
PATHOLOGY
DISEASE
Neurology & Neurosurgery
1109 Neurosciences
Publication Status: Published
Online Publication Date: 2021-06-19
Appears in Collections:Faculty of Medicine
Department of Brain Sciences



This item is licensed under a Creative Commons License Creative Commons