Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain
File(s)
Published version
Author(s)
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.
Date Issued
2021-10
Date Acceptance
2021-06-09
Citation
GLIA, 2021, 69 (10), pp.2447-2458
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.
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
Medical Research Council (MRC)
National Institute for Health Research
UK DRI Ltd
UK DRI Ltd
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000663333000001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
MR/N026934/1
RDA26
4050641385
DRI-DSI2020-001
MR/N008219/1
Subjects
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
Publication Status
Published
Date Publish Online
2021-06-19