title: Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging.
abstract: Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, [(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2-[(18)F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide] and [(11)C]SSR180575 (7-chloro-N,N-dimethyl-5-[(11)C]methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale, MIRCen and CNRS, URA2210 (I2BM), 92260 Fontenay-aux-Roses, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lavisse
authors.forename: Martine
authors.initials: M
authors.lastname: Guillermier
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hérard
authors.forename: Fanny
authors.initials: F
authors.lastname: Petit
authors.forename: Marion
authors.initials: M
authors.lastname: Delahaye
authors.forename: Nadja
authors.initials: N
authors.lastname: Van Camp
authors.forename: Lucile
authors.initials: L
authors.lastname: Ben Haim
authors.forename: Vincent
authors.initials: V
authors.lastname: Lebon
authors.forename: Philippe
authors.initials: P
authors.lastname: Remy
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Thierry
authors.initials: T
authors.lastname: Delzescaux
authors.forename: Gilles
authors.initials: G
authors.lastname: Bonvento
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Carole
authors.initials: C
authors.lastname: Escartin
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001253:Astrocytes / Q000000981:diagnostic imaging* / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D000081:Acetamides; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D020934:Ciliary Neurotrophic Factor; D019788:Fluorodeoxyglucose F18; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D008840:Microfilament Proteins; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C100745:Aif1 protein, rat; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C456740:SSR180575; C069997:Tspo protein, rat