TY - JOUR
T1 - Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation
AU - Vicente-Rodríguez, Marta
AU - Singh, Nisha
AU - Turkheimer, Federico
AU - Peris-Yague, Alba
AU - Randall, Karen
AU - Veronese, Mattia
AU - Simmons, Camilla
AU - Karim Haji-Dheere, Abdul
AU - Bordoloi, Jayanta
AU - Sander, Kerstin
AU - Awais, Ramla O
AU - Årstad, Erik
AU - Consortium, Nima
AU - Cash, Diana
AU - Parker, Christine A
N1 - Funding Information:
Anti-TSPO antibody (NP-155) was a generous gift from Dr Makoto Higuchi from the National Institutes for Quantum and Radiological Science, Japan. We thank the Wohl Cellular Imaging Centre at King's College London for help with microscopy. Figures were created with Adobe Illustrator 24.2.3 (Adobe Inc.).
Funding Information:
This study was part funded by GSK and a grant from the Wellcome Trust (Grant number: 104025/Z/14/Z). The Centre for Radiopharmaceutical Chemistry is funded in part by the Department of Health’s NIHR Biomedical Research Centres funding scheme; K. Sander is additionally funded by Mallinckrodt.
Publisher Copyright:
© 2021 The Authors
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. One reason for this could be because the interpretation of TSPO PET signal remains challenging, given the cellular heterogeneity and ubiquity of TSPO in the brain. The aim of the current study was to ascertain if TSPO PET imaging can be used to detect neuroinflammation induced by a peripheral treatment with a low dose of the endotoxin, lipopolysaccharide (LPS), in a rat model (ip LPS), and investigate the origin of TSPO signal changes in terms of their cellular sources and regional distribution. An initial pilot study utilising both [
18F]DPA-714 and [
11C]PK11195 TSPO radiotracers demonstrated [
18F]DPA-714 to exhibit a significantly higher lesion-related signal in the intracerebral LPS rat model (ic LPS) than [
11C]PK11195. Subsequently, [
18F]DPA-714 was selected for use in the ip LPS study. Twenty-four hours after ip LPS, there was an increased uptake of [
18F]DPA-714 across the whole brain. Further analyses of regions of interest, using immunohistochemistry and RNAscope Multiplex fluorescence V2 in situ hybridization technology, showed TSPO expression in microglia, monocyte derived-macrophages, astrocytes, neurons and endothelial cells. The expression of TSPO was significantly increased after ip LPS in a region-dependent manner: with increased microglia, monocyte-derived macrophages and astrocytes in the substantia nigra, in contrast to the hippocampus where TSPO was mostly confined to microglia and astrocytes. In summary, our data demonstrate the robust detection of peripherally-induced neuroinflammation in the CNS utilising the TSPO PET radiotracer, [
18F]DPA-714, and importantly, confirm that the resultant increase in TSPO signal increase arises mostly from a combination of microglia, astrocytes and monocyte-derived macrophages.
AB - The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. One reason for this could be because the interpretation of TSPO PET signal remains challenging, given the cellular heterogeneity and ubiquity of TSPO in the brain. The aim of the current study was to ascertain if TSPO PET imaging can be used to detect neuroinflammation induced by a peripheral treatment with a low dose of the endotoxin, lipopolysaccharide (LPS), in a rat model (ip LPS), and investigate the origin of TSPO signal changes in terms of their cellular sources and regional distribution. An initial pilot study utilising both [
18F]DPA-714 and [
11C]PK11195 TSPO radiotracers demonstrated [
18F]DPA-714 to exhibit a significantly higher lesion-related signal in the intracerebral LPS rat model (ic LPS) than [
11C]PK11195. Subsequently, [
18F]DPA-714 was selected for use in the ip LPS study. Twenty-four hours after ip LPS, there was an increased uptake of [
18F]DPA-714 across the whole brain. Further analyses of regions of interest, using immunohistochemistry and RNAscope Multiplex fluorescence V2 in situ hybridization technology, showed TSPO expression in microglia, monocyte derived-macrophages, astrocytes, neurons and endothelial cells. The expression of TSPO was significantly increased after ip LPS in a region-dependent manner: with increased microglia, monocyte-derived macrophages and astrocytes in the substantia nigra, in contrast to the hippocampus where TSPO was mostly confined to microglia and astrocytes. In summary, our data demonstrate the robust detection of peripherally-induced neuroinflammation in the CNS utilising the TSPO PET radiotracer, [
18F]DPA-714, and importantly, confirm that the resultant increase in TSPO signal increase arises mostly from a combination of microglia, astrocytes and monocyte-derived macrophages.
UR - http://www.scopus.com/inward/record.url?scp=85107444775&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2021.05.025
DO - 10.1016/j.bbi.2021.05.025
M3 - Article
C2 - 34052363
SN - 0889-1591
VL - 96
SP - 154
EP - 167
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -